{ "schema": "sma-public-explorer-v1", "version": "ag2-source-contexts-2026-11-14-v1", "sourceVersion": "public-capture-2026-11-03+ag2-source-contexts-2026-11-14", "updatedAt": "2026-11-14", "coverageNote": "Eleven source-linked AG2 contexts; an extract from the existing Explorer, not a replacement for the older archive.", "limitations": [ "Research navigation and assay-specific observations do not predict SMA treatment efficacy.", "Shared studies, libraries and models are not independent confirmation.", "Candidate observations originate from a historical producer snapshot; the capture date does not imply new measurements." ], "candidates": [], "contexts": [ { "id": "ag2-smn2-expression", "title": "AlphaGenome 2 (AG2): SMN2 allele and expression-model context", "category": "rna", "axisIds": [ "A13", "A43" ], "summary": "Existing natural-allele cohort associations and AlphaGenome 2 GeneMaskLFCScorer outputs are shown as distinct evidence. The model reports small DIFF_MEAN values across a shared chr5 interval; these are predictions, not measured RNA changes.", "limitations": [ "A44G has an AG1/AG2 sign disagreement; the AG1 serving equation and a common effect scale are unresolved.", "A549G in CL:0000100 is missing and was not recovered; values for that channel in other alleles are imputed_supported.", "C1 is heterogeneous adult tissue, not isolated SMA motor neurons. Phase, causal effect, training overlap, and gene-mask annotation equivalence remain unresolved." ], "sections": [ { "heading": "Source and interpretation", "text": "The Ruhno allele set provides allele identities and cohort associations, not isolated allele interventions. In the model output, observed describes channel provenance; it does not mean the variant effect was experimentally observed. A gene-first follow-up asks which sequence contributes to the expression objective; attribution is not the fraction of expression explained." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "GeneMaskLFCScorer DIFF_MEAN, common interval GRCh38 chr5:[69551712,70600288)", "columns": [ "Allele", "C1 adult tissue UBERON:0006469", "In-vitro motor neuron CL:0000100", "Channel status" ], "rows": [ [ "A-549G; GRCh38 chr5:70075972 A>G", 0.0017555952, null, "motor-neuron value not recoverably saved" ], [ "A-44G; GRCh38 chr5:70076477 A>G", 0.0029186606, 0.0025262833, "C1 observed; motor-neuron imputed_supported" ], [ "C-1897T; GRCh38 chr5:70074624 C>T", 0.00044804811, 0.0006043911, "C1 observed; motor-neuron imputed_supported" ], [ "C-478T; GRCh38 chr5:70076043 C>T", -0.0001321435, -0.00032401085, "C1 observed; motor-neuron imputed_supported" ] ], "totalRows": 4 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-smn2-expression" }, { "label": "Ruhno et al. 2019 — allele-count associations, not isolated RNA effects", "url": "https://doi.org/10.1007/s00439-019-01983-0" }, { "label": "Wu et al. 2017 — distinct promoter backgrounds and minigenes", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5886194/" } ], "reportIds": [], "specialist": false }, { "id": "ag2-smn2-gao-splicing", "title": "AlphaGenome 2 (AG2): SMN2 intron 7 +11: minigene and splice-model context", "category": "rna", "axisIds": [ "A13", "A16" ], "summary": "Gao HEK293 shortened-minigene PSI measurements differ by substitution: C>A increased inclusion while C>G reduced it. Native-genome AG2 outputs have mixed signal and fraction behavior and do not reproduce a measured PSI endpoint. Separate c.840T>C and c.859G>C positive-source comparisons and A-44G are included with their counterfindings.", "limitations": [ "The native substitutions are not authenticated as identical to the complete shortened minigene constructs.", "For both substitutions, donor and acceptor fractions increase while raw junction changes are mixed; competing-junction decline, especially skip J68, drives the fraction arithmetic.", "These model outputs are not measured PSI, rescue, or causal mechanism evidence; the diagnostic decomposition is post hoc on the same responses." ], "sections": [ { "heading": "Comparison boundary", "text": "The source assay is a HEK293 minigene. The AG2 prediction uses native genomic context and predicted junction outputs. Cell, construct, and endpoint differ, so the values are not a direct validation comparison. A source-matched measured endpoint is the next useful evidence." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." }, { "heading": "Additional source-positive comparisons", "text": "The same C1 spinal-cord configuration gives the expected inclusion-support direction for c.840T>C, but the opposite direction for source-positive c.859G>C. A-44G has no matched isolated-allele negative-control assay here. This does not establish calibrated splice-effect prediction. C1 spinal tissue and the HEK293 minigene are different contexts." } ], "tables": [ { "caption": "Source PSI and AG2 splice outputs", "columns": [ "Variant", "Source WT PSI", "Source mutant PSI", "Source change (percentage points)", "AG2 donor fraction delta", "AG2 acceptor fraction delta", "AG2 raw J78 delta" ], "rows": [ [ "GRCh38 chr5:70076585 C>A", "30/30%", "36/42%", "+6/+12", 0.0001676476415, 0.0001145921, 0.018858433 ], [ "GRCh38 chr5:70076585 C>G", "36/36%", "13/12%", "-23/-24", 0.0001671819187, 9.825900492e-05, -0.036650658 ] ], "totalRows": 2 }, { "caption": "Additional SMN2 comparisons — dimensionless ALT-minus-REF model fractions", "columns": [ "Variant, GRCh38", "Donor fraction delta", "Acceptor fraction delta", "Raw skip J68 delta" ], "rows": [ [ "chr5:70076526 T>C; c.840T>C", 0.000411945, 0.000317259, -0.001325493 ], [ "chr5:70076545 G>C; c.859G>C", -6.16352e-05, -3.99711e-05, 0.000188802 ], [ "chr5:70076477 A>G; A-44G", 6.43895e-05, 6.28495e-05, -0.000279916 ] ], "totalRows": 3 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-smn2-gao-splicing" }, { "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8789036/", "label": "Gao et al. primary source" }, { "label": "Wu et al. — source-specific SMN2 variant and construct context", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5886194/" } ], "reportIds": [], "specialist": false }, { "id": "ag2-pls3-rs73226811", "title": "AlphaGenome 2 (AG2): PLS3 rs73226811: eQTL and RNA-model context", "category": "rna", "axisIds": [ "A44" ], "summary": "The exact GRCh38 chrX:116225577 C>A allele is rs73226811. A GTEx v8 Testis conditional eQTL reports NES +0.0769585; AG2 DIFF_MEAN is negative in Testis and slightly positive in an imputed_supported motor-neuron channel.", "limitations": [ "The eQTL is an association that may reflect linkage disequilibrium or conditioning, not an isolated-allele causal effect.", "Fine-mapping returned zero records in the queried endpoint; this does not establish that fine-mapping evidence is absent.", "Five assay labels are correlated outputs, not independent replications; possible GTEx training overlap remains unresolved. No motor-neuron effect or SMA protection is established." ], "sections": [ { "heading": "Identity and context", "text": "PLS3-AS1 is a distinct gene and is not combined with PLS3. The gene-centered model window does not attribute this distal allele; an exact linked distal source or a separately documented mechanism would be needed." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "Exact allele source and model values", "columns": [ "Context", "Value", "Interpretation" ], "rows": [ [ "GTEx v8 Testis conditional eQTL", "NES +0.0769585", "Association; rank 2; tssDistance 664403" ], [ "AG2 Testis UBERON:0000473", "DIFF_MEAN -0.00096169114", "Observed channel provenance" ], [ "AG2 in-vitro motor neuron CL:0000100", "DIFF_MEAN +0.00008480996", "Imputed_supported channel" ] ], "totalRows": 3 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-pls3-rs73226811" }, { "label": "GTEx v8 exact PLS3/Testis conditional eQTL source", "url": "https://gtexportal.org/api/v2/association/independentEqtl?datasetId=gtex_v8&gencodeId=ENSG00000102024.17&tissueSiteDetailId=Testis&itemsPerPage=100" } ], "reportIds": [], "specialist": false }, { "id": "ag2-smn2-gene-first", "title": "AlphaGenome 2 (AG2): SMN2 gene-first sequence attribution", "category": "rna", "axisIds": [ "A43" ], "summary": "Two reference RNA-expression attribution maps identify a shared leading TSS/first-exon tile. The terminal-exon tile ranks second in C1 spinal tissue and third in the in-vitro motor-neuron context; an internal-exon tile ranks second in the latter. These are sequence-attribution maps, not measured regulatory effects.", "limitations": [ "High attribution overlaps RNA objective exons and does not identify an enhancer.", "Attribution shares are not fractions of expression explained; no null or functional perturbation is available." ], "sections": [ { "heading": "Next source question", "text": "Separate exonic from non-exonic attribution in the two specified follow-up regions and reuse existing CAGE, PRO-cap, and accessible-chromatin evidence by coordinate before considering any additional inference." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "GRCh38 half-open 500-bp attribution regions", "columns": [ "Context", "Rank", "Region", "Annotated overlap" ], "rows": [ [ "Both objectives", 1, "chr5:[70049500,70050000)", "TSS and 98 bp of first exon" ], [ "C1 spinal tissue", 2, "chr5:[70077000,70077500)", "482 bp of terminal exon" ], [ "In-vitro motor neurons", 3, "chr5:[70077000,70077500)", "482 bp of terminal exon" ], [ "In-vitro motor neurons", 2, "chr5:[70067000,70067500)", "287 bp of internal exons" ] ], "totalRows": 4 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-smn2-gene-first" }, { "label": "AlphaGenome 2 reference-gradient API — method definition", "url": "https://www.alphagenomedocs.com/api/generated/alphagenome.models.v2.dna_client.DnaClient.predict_interval_gradients.html" } ], "reportIds": [], "specialist": false }, { "id": "ag2-smn2-regulatory-sources", "title": "AlphaGenome 2 (AG2): SMN2 regulatory-coordinate and chromatin context", "category": "rna", "axisIds": [ "A43" ], "summary": "Three fixed regulatory intervals were cross-checked against six distinct donor ATAC experiments, comprising three healthy and three ALS donors. No selected conservative peak overlaps were found; this is a bounded source-selection result, not evidence of biological inactivity.", "limitations": [ "The experiments contain no SMA donors and do not establish SMN2 target-gene causality.", "A shared exclusion mask overlaps none of the three intervals, so this specific mask does not explain the zero selected overlaps; broader activity and other sources remain untested." ], "sections": [ { "heading": "Interpretation", "text": "The coordinate overlap check does not test whether the regions regulate SMN2 in relevant cells. It only reports the selected interval and peak comparison." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "Fixed intervals and selected ATAC comparison", "columns": [ "Source set", "Donors", "Selected conservative peak overlap", "Scope" ], "rows": [ [ "Six donor ATAC experiments", "3 healthy; 3 ALS", "0 at all three fixed intervals", "No SMA donors; not an inactivity result" ] ], "totalRows": 1 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-smn2-regulatory-sources" }, { "label": "ENCODE motor-neuron ATAC experiment ENCSR410DWV — one of the six source experiments", "url": "https://www.encodeproject.org/experiments/ENCSR410DWV/" } ], "reportIds": [], "specialist": false }, { "id": "ag2-mdm4-topology", "title": "AlphaGenome 2 (AG2): MDM4 reference splice topology and sample-source boundary", "category": "rna", "axisIds": [ "A13" ], "summary": "Reference splice-event summaries, local junction edges, strict read paths, and six named BAM paths describe different evidence units. Their coordinate topology can be compared, but they do not establish a selective MDM4 isoform switch in the SMA cell line.", "limitations": [ "Generic primary dermal fibroblasts and static reference DNA do not match GM03813 SMA or treatment.", "Individual edges are not phased chains. SE event counts and A3SS choices cannot be converted directly into three isoform fractions.", "The exact run build, processing options, input hashes, and event membership for the six BAM paths remain unbound; do not join the separately named paths to sample effects." ], "sections": [ { "heading": "Counterfinding", "text": "The same named edges can have event-specific counts. SE inclusion counts are not the sum of two edge columns, and A3SS inclusion evidence spans a short boundary. Strict read-name groups are separately filtered local assignments, not validated phased transcripts." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." }, { "heading": "Relationship to the existing human RNA observations", "text": "The source cohort contains 15 deposited libraries from one GM03813 fibroblast line. Local 68-nt, 39-nt and skip paths are separate alignment evidence. A processing log naming six BAM paths does not authenticate their input contents or join AG2 reference edges to sample-level treatment effects. Original event membership and denominators remain unresolved." } ], "tables": [ { "caption": "Distinct evidence units retained", "columns": [ "Evidence unit", "What it supports", "What it does not establish" ], "rows": [ [ "Reference splice event", "Event-level inclusion or choice", "Local read paths or isoform fractions" ], [ "Reference junction edge", "Coordinate topology", "Phased transcript chain" ], [ "Strict joined read path", "Filtered local assignment", "Historical run membership or sample effect" ], [ "Six BAM path names", "Names recorded in processing log", "Verified sample-level quantitative join" ] ], "totalRows": 4 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-mdm4-topology" }, { "label": "Human MDM4 local RNA alternatives — existing methods and results with original sources", "url": "https://sma-research.info/api/v2/research/axis-dossiers/sources/ec91ba2d55c4e7977332" } ], "reportIds": [], "specialist": false }, { "id": "ag2-pls3-gene-first", "title": "AlphaGenome 2 (AG2): PLS3 reference annotation and gene-first model context", "category": "rna", "axisIds": [ "A44" ], "summary": "PLS3 reference annotations differ by Ensembl release. A gene-first splice scorer returned four alternative edges as not_returned and a positive canonical edge score; neither result establishes absence of alternative splicing or a measured expression change.", "limitations": [ "Release 112 and release 116 annotations differ; exonic overlap cannot be treated as a biological change.", "not_returned is not a zero score or absence claim. No exact junction counts were supplied in the inspected experiment files.", "Transcript quantification tables represent two biological replicate labels and two output methods, not four independent samples; newer alternative stable IDs are absent from the target catalogs." ], "sections": [ { "heading": "Existing RNA evidence", "text": "Four verified transcript-quantification tables from one ENCODE motor-neuron experiment include PLS3.17 and canonical-stable ENST00000355899.7. Exact coordinate-bound junction counts are the next relevant measured source; keep assay and phasing explicit." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "Distinct PLS3 reference regions — GRCh38 half-open", "columns": [ "Context", "Region", "Selection rank", "Boundary" ], "rows": [ [ "C1 spinal tissue; GTEx polyA RNA", "chrX:[115603000,115603500)", 1, "500 bp; 90 bp exon overlap in release 116" ], [ "In-vitro motor neuron; ENCODE total RNA", "chrX:[115563500,115564000)", 2, "500 bp; rank 1 lies in excluded control window;139 bp exon overlap in release116" ] ], "totalRows": 2 }, { "caption": "Reference annotation and model output", "columns": [ "Measure", "Release/result", "Interpretation" ], "rows": [ [ "Exonic overlap", "Release 112: 0 bp in both selected regions; release 116: 90 bp in C1 and 139 bp in motor neurons", "Reference annotation only" ], [ "Alternative splice edges", "4 not_returned", "Not an absence or zero result" ], [ "Canonical edge", "1.958001852", "Model score; not measured PSI" ] ], "totalRows": 3 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-pls3-gene-first" }, { "label": "ENCODE ENCSR319GRO — retained motor-neuron RNA source", "url": "https://www.encodeproject.org/experiments/ENCSR319GRO/" } ], "reportIds": [], "specialist": false }, { "id": "ag2-perp-arfgef3", "title": "AlphaGenome 2 (AG2): PERP and ARFGEF3: neuronal regulatory-source context", "category": "rna", "axisIds": [ "A21" ], "summary": "The fixed PERP-linked element EH38E2507697 has a verified neuronal assay connection, but target-gene causality remains open. A nearby shared 450 bp element has multiple target IDs, including PERP and ARFGEF3; spatial overlap and model attribution do not establish exclusive regulation.", "limitations": [ "Human SMA/control PERP ranges overlap; donor mapping and processing remain unresolved. Separate NGN2 comparison is adjusted P=.929.", "The motor-neuron assay source includes one ALS donor; iNPC/iPSC-derived motor-neuron biosamples differ. CTCF is missing and no displayed target-link result confirms PERP causality.", "No selected thresholded peak overlaps the original cCRE/tile/fixed ±5 kb regions; this is not evidence of zero activity. The shared element is not target-specific." ], "sections": [ { "heading": "Strongest counterfinding", "text": "At EH38E2507697, the reported neuronal source values are ATAC z=1.34, H3K4me3 z=-0.12, H3K27ac z=-0.56, with CTCF missing. The source establishes a neuronal measurement connection, not an active enhancer or PERP functional link. The adjacent ARFGEF3 evidence also remains non-specific." }, { "heading": "Next source question", "text": "Identify exact biosamples and files for the element and obtain measured neuronal PERP transcript or 3D linkage with target identity. Preserve the PERP.12 versus current .13 annotation distinction." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." }, { "heading": "A separate 450-bp source-selected element", "text": "At GRCh38 chr6:[138115850,138116300), the EPIraction source contains eight target-gene IDs including PERP and ARFGEF3. This is a different region from EH38E2507697. A separately requested ARFGEF3 RNA attribution map has about 2.98-fold mean absolute attribution versus each immediate same-width flank; the element contributes 0.0978818% of the absolute attribution in that returned window. Different gene-centered windows prevent a cross-gene effect comparison. An exact allele or target-resolved functional observation is needed to distinguish target hypotheses." }, { "heading": "Context comparability", "text": "The additional dermal-fibroblast RNA attribution used a minus-strand track, whereas the motor-neuron RNA track was unstranded. Their numerical difference is not an isolated cell-type effect. These DNA/RNA regulatory comparisons do not test the separate PERP–DAG1 protein-interaction hypothesis." } ], "tables": [ { "caption": "Bounded source and model findings", "columns": [ "Finding", "Result", "Boundary" ], "rows": [ [ "SCREEN neuronal element", "ATAC z 1.34; H3K4me3 z -0.12; H3K27ac z -0.56; CTCF missing", "Ancillary collection; no target-link result" ], [ "ATAC cCRE/flank ratio", "5.686308134", "Model consistency, not independent validation" ], [ "H3K27ac cCRE/flank ratio", "0.867984887", "No local elevation in this comparison" ], [ "Shared element", "450 bp; eight target IDs", "No exclusive PERP or ARFGEF3 assignment" ] ], "totalRows": 4 }, { "caption": "Separate source-selected ARFGEF3-map question", "columns": [ "Fixed region, GRCh38 half-open", "Local mean-absolute-attribution ratios", "Own-window absolute-attribution share", "Source target identities" ], "rows": [ [ "chr6:[138115850,138116300)", "2.98160 versus left flank;2.98040 versus right flank", "0.0978818%", "8 target-gene IDs; not an exclusive PERP enhancer" ] ], "totalRows": 1 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-perp-arfgef3" }, { "label": "ENCODE EPIraction ENCSR714BPP — multi-target source annotation", "url": "https://www.encodeproject.org/experiments/ENCSR714BPP/" }, { "label": "ENCODE H3K4me3 ENCSR503HWR — distinct neuronal source context", "url": "https://www.encodeproject.org/experiments/ENCSR503HWR/" } ], "reportIds": [], "specialist": false }, { "id": "ag2-hspa8-mouse-cis", "title": "AlphaGenome 2 (AG2): Mouse Hspa8 cis-RNA prediction", "category": "rna", "axisIds": [ "A44" ], "summary": "For the mouse Hspa8 G470R allele, one paired broad-brain prediction returned small raw-score ratios for fixed upstream and downstream junctions. A separate diagnostic skip ratio is larger but uses a low reference score. This does not establish a cis-RNA effect.", "limitations": [ "These are small, uncalibrated raw model-score differences in broad brain, not PSI or measured RNA.", "The cis-RNA question is distinct from protein-level and transcript-level mouse context; no biological absence is established." ], "sections": [ { "heading": "Context separation", "text": "The source mouse allele is mm10 chr9:40804249 G>C, p.Gly470Arg. NM_031165.5:c.1408G>C is our current annotation crosswalk, not an original-paper transcript version. The prediction uses broad mouse brain UBERON:0000955, ENCODE polyA RNA; this is not an SMA motor-neuron or developmental-stage model. The known protein-level and SMN2-trans observations are separate from this local Hspa8 cis-RNA question." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "Paired mouse Hspa8 junction prediction", "columns": [ "Output", "ALT/REF ratio or score", "Interpretation" ], "rows": [ [ "Fixed upstream junction", "1.024758041", "Raw score ratio" ], [ "Fixed downstream junction", "1.018436649", "Raw score ratio" ], [ "Diagnostic skip junction", "1.068795042; REF 0.007807408; absolute delta 0.000537111", "Low reference score; diagnostic only" ] ], "totalRows": 3 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-hspa8-mouse-cis" }, { "label": "Kim et al., Neuron 2023 — mouse Hspa8 modifier source", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10164130/" } ], "reportIds": [], "specialist": false }, { "id": "ag2-pls3-blood-c367", "title": "AlphaGenome 2 (AG2): Reported PLS3 c.367+182C>T blood association", "category": "rna", "axisIds": [ "A44" ], "summary": "A reported association links PLS3 c.367+182C>T to blood expression in a 50-person SMA and 21-control cohort. The genomic coordinate, transcript identity, carrier count, and original supplement were not established, so no AG2 variant call was made.", "limitations": [ "The exact variant identity is unresolved; no genomic coordinate or transcript is inferred.", "The reported blood association has no bound carrier count and no consistent clinical benefit.", "Venous-blood reference RNA differs from full-length ddPCR; a literal blood RNA label was imputed. This is not a motor-neuron result." ], "sections": [ { "heading": "Next source question", "text": "Recover the original supplement and bind the exact transcript and genomic allele before considering any variant-level model comparison. Keep this candidate separate from rs73226811." }, { "heading": "Reported association and strongest counterfinding", "text": "The source reports p=0.04 and a carrier median of 19.1 copies/ng cDNA. The pooled 10.8 value is inconsistently labelled mean or median and is not an authenticated noncarrier comparator. Carrier count is not bound. Family severity directions differ, and higher expression does not establish consistent clinical benefit." } ], "tables": [ { "caption": "Reported cohort context", "columns": [ "Item", "Reported information", "Status" ], "rows": [ [ "Cohort", "50 SMA; 21 controls", "Source report" ], [ "Variant", "PLS3 c.367+182C>T", "Genomic identity pending" ], [ "Carrier count", "Not bound", "Missing" ], [ "AG2 result", "None", "No call made" ] ], "totalRows": 4 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-pls3-blood-c367" }, { "label": "Published PLS3 blood association — original study", "url": "https://doi.org/10.1212/NXG.0000000000000386" } ], "reportIds": [], "specialist": false }, { "id": "ag2-smn1-c863", "title": "AlphaGenome 2 (AG2): SMN1 c.863G>T splice-source and model context", "category": "rna", "axisIds": [ "A13" ], "summary": "SMN1 NM_000344.3 c.863G>T maps to GRCh38 chr5:70951969 G>T. The shortened HEK293 minigene showed exon 7 inclusion decreasing from 91.7% to 14.8%; native blood and fibroblast observations are separate materials. AG2 fraction changes are tiny and negative while raw J78 rises in all three imputed channels.", "limitations": [ "The model fraction changes are only 0.0055–0.0173 percentage points and are not PSI; rising raw J78 is compatible with falling J78 fraction because the denominator also rises.", "Native RNA observations are not a matched model denominator and no quantitative conversion is established.", "SMN1 and SMN2 remain distinct paralogs; do not infer SMN2 behavior from this result." ], "sections": [ { "heading": "Bounded interpretation", "text": "This is a source/model comparison, not reproduction of the strong experimental splice effect. The finite reference-transfer question is closed; the useful next evidence would be source-bound human native-RNA allele/junction data with material and denominator specified." }, { "heading": "Model and output provenance", "text": "These are API predictions made with the AlphaGenome 2 client. ALL_FOLDS is the requested model selector; an immutable served weight revision was not independently supplied. Channel labels such as observed or imputed describe output provenance, not an experiment on the variant. Model outputs and source measurements retain their own units and denominators." } ], "tables": [ { "caption": "Source and model comparison", "columns": [ "Evidence", "Result", "Context" ], "rows": [ [ "HEK293 shortened minigene", "Exon 7 inclusion 91.7% to 14.8%", "Experimental construct" ], [ "AG2 inclusion-support fractions", "Negative changes across 3 channels; 0.0055–0.0173 percentage points", "Coupled imputed channels" ], [ "AG2 raw J78", "Increases in all 3 channels", "Raw junction score, not PSI" ], [ "Native RNA", "Blood from 2 patients; fibroblast from 1 patient", "Distinct source materials; no matched denominator" ] ], "totalRows": 4 }, { "caption": "HEK293 imputed model channels — ALT-minus-REF fractions expressed in percentage points", "columns": [ "Channel", "Exon6→7 donor-fraction delta, percentage points", "Exon7→8 acceptor-fraction delta, percentage points", "Raw Exon7→8 score delta" ], "rows": [ [ "EFO:0001182_polyA plus RNA-seq-encode", -0.016478974785794076, -0.005892535390228382, 0.013494253158569336 ], [ "EFO:0001182_polyA plus RNA-seq-gtex", -0.015993906385081136, -0.005529493163225485, 0.006148219108581543 ], [ "EFO:0001182_total RNA-seq-encode", -0.017294536118261927, -0.009531910480797823, 0.007289528846740723 ] ], "totalRows": 3 } ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-smn1-c863" }, { "url": "https://doi.org/10.1038/ejhg.2015.213", "label": "SMN1 c.863G>T primary source" } ], "reportIds": [], "specialist": false } ], "variants": [ { "id": "ag2-smn1-c863g-t", "title": "SMN1 c.863G>T", "gene": "SMN1", "coordinate": "GRCh38 chr5:70951969 G>T; NM_000344.3:c.863G>T", "axisIds": [ "A13" ], "summary": "A shortened HEK293 minigene showed exon 7 inclusion falling from 91.7% to 14.8%. AG2 inclusion-support fraction changes are tiny and negative across three imputed channels, while raw J78 rises; this is not measured PSI or a quantitative reproduction of the source effect.", "limitations": [ "Native blood and fibroblast RNA are distinct source materials and do not supply a matched denominator.", "SMN1 is kept distinct from SMN2; the model outputs are not measured RNA." ], "references": [ { "label": "SMN1 c.863G>T source and model context", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-smn1-c863" }, { "url": "https://doi.org/10.1038/ejhg.2015.213", "label": "Primary source" } ], "contextId": "ag2-smn1-c863" }, { "id": "ag2-mouse-hspa8-g470r", "title": "Mouse Hspa8 G470R", "gene": "Hspa8", "coordinate": "GRCm38/mm10 chr9:40804249 G>C; NM_031165.5:c.1408G>C annotation crosswalk", "axisIds": [ "A44" ], "summary": "One paired broad-brain prediction returned small raw-score ratios for fixed Hspa8 junctions; the diagnostic skip ratio uses a low reference score. The outputs do not establish a measured cis-RNA effect.", "limitations": [ "The prediction is uncalibrated and is not PSI or measured RNA.", "Keep this mouse cis-RNA question separate from protein and transcript contexts." ], "references": [ { "label": "Source-linked methods, model results and interpretation limits", "url": "https://sma-research.info/research-artifacts/alphagenome2-source-linked-20261114/#ag2-hspa8-mouse-cis" }, { "label": "Kim et al., Neuron 2023 — mouse Hspa8 modifier source", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10164130/" } ], "contextId": "ag2-hspa8-mouse-cis" } ] }