Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.733A>G | N245D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (six pathogenic vs five benign) and the consensus of high‑accuracy methods lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -7.847 | In-Between | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.0 | 0.09 | Likely Benign | 0.18 | Likely Benign | 0.79 | Ambiguous | 0.712 | Likely Pathogenic | -3.62 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.84 | Benign | 0.13 | Tolerated | 0.1953 | 0.4599 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.655T>C | C219R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 13 tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.00 | Destabilizing | 1.5 | 2.20 | Destabilizing | 2.60 | Destabilizing | 1.33 | Destabilizing | 0.904 | Likely Pathogenic | -9.90 | Deleterious | 0.969 | Probably Damaging | 0.680 | Possibly Damaging | 5.80 | Benign | 0.00 | Affected | 0.1381 | 0.1837 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.743G>T | R248L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and FATHMM, whereas the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for R248L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -12.110 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.5 | 0.01 | Likely Benign | 0.57 | Ambiguous | 0.67 | Ambiguous | 0.825 | Likely Pathogenic | -6.06 | Deleterious | 0.979 | Probably Damaging | 0.680 | Possibly Damaging | 5.66 | Benign | 0.03 | Affected | 0.1616 | 0.4741 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1910C>A | S637Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of individual predictors (seven versus five) lean toward pathogenicity, and the consensus‑based SGM‑Consensus also supports a likely pathogenic classification. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -12.633 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 0.13 | Likely Benign | 0.1 | 1.52 | Ambiguous | 0.83 | Ambiguous | 0.50 | Likely Benign | 0.209 | Likely Benign | -3.78 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.00 | Affected | 0.0968 | 0.4071 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1910C>T | S637F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a pathogenic verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -13.266 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.01 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.49 | Likely Benign | 0.49 | Likely Benign | 0.222 | Likely Benign | -3.92 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 0.0780 | 0.4126 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.3520G>C | E1174Q 2D  AIThe SynGAP1 missense variant E1174Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta results are unavailable. Based on the overall distribution of predictions and the consensus from high‑accuracy tools, the variant is most likely benign. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -3.778 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.323 | Likely Benign | -1.04 | Neutral | 0.959 | Probably Damaging | 0.681 | Possibly Damaging | 5.43 | Benign | 0.03 | Affected | 0.0936 | 0.6268 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.550G>A | E184K 2D  AIThe SynGAP1 missense variant E184K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that E184K is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -14.037 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -3.31 | Deleterious | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.2890 | 0.8227 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.583G>A | A195T 2D  AIThe SynGAP1 missense variant A195T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, which would provide a protein‑folding stability estimate, has no available output for this variant. Overall, the preponderance of evidence indicates that A195T is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -7.060 | In-Between | 0.883 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | -2.09 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 4.08 | Benign | 0.14 | Tolerated | 0.0937 | 0.6006 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.608A>G | D203G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D203G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (two benign vs. one pathogenic, one uncertain); and Foldetta also predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a benign effect, and this is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -6.332 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.40 | Likely Benign | 0.03 | Likely Benign | 0.231 | Likely Benign | -3.42 | Deleterious | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 0.2708 | 0.4312 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.713A>C | E238A 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant E238A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM predicts benign, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence indicates that E238A is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -13.252 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.3 | 1.89 | Ambiguous | 1.40 | Ambiguous | 0.57 | Ambiguous | 0.879 | Likely Pathogenic | -5.44 | Deleterious | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.44 | Benign | 0.04 | Affected | 0.4164 | 0.5610 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.745G>T | A249S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. Protein‑stability assessments are mixed: FoldX indicates a benign effect, while Rosetta and Foldetta are uncertain. High‑accuracy predictions show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence—including the high‑accuracy tools—suggests that A249S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -5.707 | Likely Benign | 0.634 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.3 | 0.84 | Ambiguous | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.465 | Likely Benign | -1.40 | Neutral | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 5.63 | Benign | 0.19 | Tolerated | 0.1962 | 0.3393 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.752A>G | K251R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Rosetta and Foldetta give uncertain results. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -4.355 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.37 | Likely Benign | 0.0 | -0.64 | Ambiguous | -0.51 | Ambiguous | 0.14 | Likely Benign | 0.531 | Likely Pathogenic | -0.61 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.92 | Benign | 0.34 | Tolerated | 0.4756 | 0.1049 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.761A>G | K254R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K254R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (2 benign vs. 1 pathogenic, 1 uncertain); Foldetta is uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -11.064 | Likely Pathogenic | 0.528 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.1 | -1.13 | Ambiguous | -0.79 | Ambiguous | 0.76 | Ambiguous | 0.604 | Likely Pathogenic | -2.36 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.81 | Benign | 0.09 | Tolerated | 0.4070 | 0.1658 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.1847A>T | D616V 2D  3DClick to see structure in 3D Viewer AISynGAP1 D616V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, and FATHMM, while pathogenic calls are made by FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic signal: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect for D616V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -13.992 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 2.41 | Destabilizing | 0.2 | 1.95 | Ambiguous | 2.18 | Destabilizing | 0.36 | Likely Benign | 0.268 | Likely Benign | -7.36 | Deleterious | 0.972 | Probably Damaging | 0.682 | Possibly Damaging | 3.26 | Benign | 0.00 | Affected | 0.0699 | 0.4393 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.2201C>G | P734R 2D  AIThe SynGAP1 missense variant P734R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -6.099 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -3.00 | Deleterious | 0.984 | Probably Damaging | 0.682 | Possibly Damaging | 2.71 | Benign | 0.07 | Tolerated | 0.1664 | 0.2464 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2597T>C | V866A 2D  AIThe SynGAP1 missense variant V866A is reported in gnomAD (ID 6‑33443149‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | 6-33443149-T-C | 1 | 6.20e-7 | -1.805 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -1.27 | Neutral | 0.889 | Possibly Damaging | 0.682 | Possibly Damaging | 2.87 | Benign | 0.37 | Tolerated | 3.82 | 4 | 0.3441 | 0.2512 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||
| c.2674T>G | S892A 2D  AIThe SynGAP1 missense variant S892A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -3.867 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.45 | Neutral | 0.889 | Possibly Damaging | 0.682 | Possibly Damaging | 2.63 | Benign | 0.02 | Affected | 0.5131 | 0.4481 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3169A>T | S1057C 2D  AIThe SynGAP1 missense variant S1057C is reported in gnomAD (ID 6‑33443721‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic impact, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-T | -7.529 | In-Between | 0.100 | Likely Benign | Likely Benign | 0.258 | Likely Benign | -0.64 | Neutral | 0.977 | Probably Damaging | 0.683 | Possibly Damaging | 5.23 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1856 | 0.6106 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.599T>C | L200S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 L200S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods give a pathogenic signal from Foldetta (protein‑folding stability analysis) while AlphaMissense‑Optimized is uncertain and thus not considered evidence. Overall, the majority of available predictions (10 pathogenic vs 4 benign) indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -10.755 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 2.72 | Destabilizing | 0.1 | 3.38 | Destabilizing | 3.05 | Destabilizing | 1.43 | Destabilizing | 0.141 | Likely Benign | -1.96 | Neutral | 0.970 | Probably Damaging | 0.683 | Possibly Damaging | 4.05 | Benign | 0.06 | Tolerated | 0.3279 | 0.0575 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||
| c.2224C>T | R742W 2D  AIThe SynGAP1 missense variant R742W is listed in ClinVar (ID 2581888.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441689‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | Uncertain | 1 | 6-33441689-C-T | 6 | 3.72e-6 | -7.725 | In-Between | 0.133 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.71 | Neutral | 0.992 | Probably Damaging | 0.684 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1638 | 0.2839 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2960A>C | D987A 2D  AIThe SynGAP1 D987A missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools that classify the change as benign include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) and the SGM‑Consensus score (Likely Pathogenic) indicate a pathogenic effect. Grouping by agreement, benign predictions are limited to two tools, while pathogenic predictions are supported by seven distinct algorithms. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a Likely Pathogenic classification, and the protein‑folding stability method Foldetta is unavailable for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.880 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.261 | Likely Benign | -3.72 | Deleterious | 0.943 | Possibly Damaging | 0.686 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 0.3930 | 0.6846 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.899C>A | S300Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300Y has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools (AlphaMissense‑Default and Rosetta) are uncertain and do not influence the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar status (none is available). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -10.464 | Likely Pathogenic | 0.422 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.4 | 0.55 | Ambiguous | 0.24 | Likely Benign | 0.28 | Likely Benign | 0.116 | Likely Benign | -2.52 | Deleterious | 0.975 | Probably Damaging | 0.686 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 0.0678 | 0.5395 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.3448G>A | A1150T 2D AIThe SynGAP1 missense variant A1150T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.467 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -2.06 | Neutral | 0.905 | Possibly Damaging | 0.687 | Possibly Damaging | 2.34 | Pathogenic | 0.03 | Affected | 0.1540 | 0.7182 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.1094T>A | V365E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365E is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. With all available evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -16.263 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.99 | Destabilizing | 0.3 | 3.81 | Destabilizing | 3.90 | Destabilizing | 2.20 | Destabilizing | 0.613 | Likely Pathogenic | -5.02 | Deleterious | 0.989 | Probably Damaging | 0.688 | Possibly Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.0849 | 0.2083 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.2025C>A | N675K 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N675K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, whereas pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported for Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -12.851 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 2.88 | Destabilizing | 1.2 | 0.06 | Likely Benign | 1.47 | Ambiguous | 0.74 | Ambiguous | 0.177 | Likely Benign | -4.75 | Deleterious | 0.993 | Probably Damaging | 0.688 | Possibly Damaging | 3.44 | Benign | 0.02 | Affected | 0.2424 | 0.6040 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2025C>G | N675K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic classification for N675K, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -12.851 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 2.88 | Destabilizing | 1.2 | 0.06 | Likely Benign | 1.47 | Ambiguous | 0.74 | Ambiguous | 0.177 | Likely Benign | -4.75 | Deleterious | 0.993 | Probably Damaging | 0.688 | Possibly Damaging | 3.44 | Benign | 0.02 | Affected | 0.2424 | 0.6040 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.214C>T | R72W 2D AIThe SynGAP1 missense variant R72W is catalogued in gnomAD (ID 6‑33425822‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign outcome. The Foldetta stability analysis is unavailable, providing no additional evidence. Overall, the preponderance of computational evidence points to a benign effect for R72W, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.455349 | Uncertain | 0.355 | 0.819 | 0.375 | 6-33425822-C-T | 1 | 6.20e-7 | -5.546 | Likely Benign | 0.430 | Ambiguous | Likely Benign | 0.145 | Likely Benign | -1.82 | Neutral | 0.994 | Probably Damaging | 0.689 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1601 | 0.3652 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2279T>G | M760R 2D  AIThe SynGAP1 missense variant M760R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -2.794 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -1.61 | Neutral | 0.975 | Probably Damaging | 0.690 | Possibly Damaging | 2.71 | Benign | 0.09 | Tolerated | 0.1804 | 0.1318 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2414T>A | L805Q 2D  AIThe SynGAP1 missense variant L805Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (2 pathogenic vs. 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. three benign predictions, with a pathogenic SGM Consensus) indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | -6.244 | Likely Benign | 0.427 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -2.66 | Deleterious | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 2.37 | Pathogenic | 0.00 | Affected | 0.1215 | 0.1265 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2564T>A | L855H 2D  AIThe SynGAP1 missense variant L855H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.485558 | Uncertain | 0.285 | 0.823 | 0.625 | -3.224 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.07 | Neutral | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 3.96 | Benign | 0.01 | Affected | 0.1137 | 0.1313 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2579T>A | V860D 2D  AIThe SynGAP1 missense variant V860D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.518121 | Binding | 0.269 | 0.803 | 0.250 | -4.310 | Likely Benign | 0.590 | Likely Pathogenic | Likely Benign | 0.164 | Likely Benign | -1.98 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 0.1382 | 0.1047 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2697C>G | I899M 2D  AIThe SynGAP1 missense variant I899M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of computational predictors and the high‑accuracy tools points to a benign impact for I899M. This conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.443727 | Uncertain | 0.292 | 0.928 | 0.375 | -3.407 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.15 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 2.70 | Benign | 0.01 | Affected | 0.0687 | 0.2489 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2969C>G | S990C 2D AIThe SynGAP1 missense variant S990C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for S990C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -5.753 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.91 | Neutral | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.73 | Benign | 0.01 | Affected | 0.1041 | 0.5823 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2992G>C | A998P 2D  AIThe SynGAP1 missense variant A998P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for A998P. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -2.220 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.40 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 0.1924 | 0.5106 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2993C>A | A998D 2D  AIThe SynGAP1 missense variant A998D is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy assessment indicates that AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome, and Foldetta data are unavailable. Overall, the majority of robust predictors lean toward a benign impact. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -5.481 | Likely Benign | 0.365 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.55 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.1754 | 0.2143 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3002T>C | L1001P 2D  AIThe SynGAP1 missense variant L1001P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | Uncertain | 1 | -3.071 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.02 | Neutral | 0.966 | Probably Damaging | 0.690 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3322 | 0.0929 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3422C>G | P1141R 2D AIThe SynGAP1 missense variant P1141R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; a Foldetta stability analysis is unavailable. Overall, the majority of computational predictions (seven pathogenic vs. three benign) support a pathogenic classification. This consensus does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.768 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.120 | Likely Benign | -3.90 | Deleterious | 0.913 | Possibly Damaging | 0.690 | Possibly Damaging | 0.97 | Pathogenic | 0.00 | Affected | 0.1329 | 0.3614 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3674C>T | S1225F 2D AIThe SynGAP1 missense variant S1225F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1225F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -7.938 | In-Between | 0.328 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.34 | Neutral | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 5.37 | Benign | 0.06 | Tolerated | 0.0505 | 0.4979 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||
| c.3692G>T | S1231I 2D  AIThe SynGAP1 missense variant S1231I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains likely pathogenic; Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification for S1231I, and this conclusion does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -9.360 | Likely Pathogenic | 0.712 | Likely Pathogenic | Likely Benign | 0.203 | Likely Benign | -3.24 | Deleterious | 0.966 | Probably Damaging | 0.690 | Possibly Damaging | 2.64 | Benign | 0.04 | Affected | 0.0701 | 0.4550 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.370G>C | A124P 2D AIThe SynGAP1 missense variant A124P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A124P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.030 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -1.19 | Neutral | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 4.05 | Benign | 0.03 | Affected | 0.2293 | 0.6141 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3890G>T | R1297M 2D  AIThe SynGAP1 missense variant R1297M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -4.286 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -3.00 | Deleterious | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.1294 | 0.2449 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3896T>C | L1299P 2D AIThe SynGAP1 missense variant L1299P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Grouping by consensus, the majority of predictors (five out of nine) favor a benign effect, and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta data are unavailable. Consequently, the variant is most likely benign according to the available computational evidence, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -2.589 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.322 | Likely Benign | -4.06 | Deleterious | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.3552 | 0.1309 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.682A>C | T228P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is inconclusive, but the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.559 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.6 | 0.47 | Likely Benign | 1.06 | Ambiguous | 0.21 | Likely Benign | 0.690 | Likely Pathogenic | -3.54 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.64 | Benign | 0.02 | Affected | 0.2207 | 0.6360 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.683C>T | T228I 2D  AIThe SynGAP1 missense variant T228I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With eight tools favoring pathogenicity versus six favoring benign, and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently contains no entry for T228I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.605 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.02 | Likely Benign | 0.6 | 0.21 | Likely Benign | 0.12 | Likely Benign | 0.23 | Likely Benign | 0.692 | Likely Pathogenic | -3.99 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.65 | Benign | 0.06 | Tolerated | 0.0951 | 0.7051 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.586T>A | L196M 2D  AIThe SynGAP1 missense variant L196M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result. Overall, more tools predict pathogenicity (5) than benignity (3), and the high‑accuracy predictions do not overturn this trend. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -8.957 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.094 | Likely Benign | -1.48 | Neutral | 0.971 | Probably Damaging | 0.691 | Possibly Damaging | 3.64 | Benign | 0.01 | Affected | 0.0689 | 0.2786 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2311T>C | S771P 2D  AIThe SynGAP1 missense variant S771P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -5.045 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -1.32 | Neutral | 0.901 | Possibly Damaging | 0.692 | Possibly Damaging | 4.03 | Benign | 0.19 | Tolerated | 0.2194 | 0.5515 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.109T>C | S37P 2D AIThe SynGAP1 missense variant S37P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for S37P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -3.788 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -1.29 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.2657 | 0.5327 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.1153T>C | S385P 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant S385P is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438058‑T‑C). Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions from FoldX and Rosetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | Uncertain | 1 | 6-33438058-T-C | -5.431 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.91 | Ambiguous | 0.6 | -0.90 | Ambiguous | 0.01 | Likely Benign | 0.19 | Likely Benign | 0.385 | Likely Benign | -0.26 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.63 | Benign | 0.04 | Affected | 4.32 | 3 | 0.2925 | 0.6805 | 1 | -1 | -0.8 | 10.04 | 210.3 | 18.5 | 1.8 | 0.9 | 0.3 | 0.0 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Pro385 is potentially tolerated in the Ω loop. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||
| c.1165T>C | S389P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389P is listed in gnomAD (variant ID 6‑33438070‑T‑C) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438070-T-C | -5.286 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 1.85 | Ambiguous | 2.0 | -0.99 | Ambiguous | 0.43 | Likely Benign | 0.16 | Likely Benign | 0.460 | Likely Benign | -0.44 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 5.05 | Benign | 0.01 | Affected | 4.32 | 8 | 0.3098 | 0.7002 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||
| c.1166C>T | S389L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389L is catalogued in gnomAD (6‑33438071‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments are consistent with the benign consensus: AlphaMissense‑Optimized reports Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438071-C-T | 7 | 4.40e-6 | -6.040 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.69 | Ambiguous | 0.37 | Likely Benign | -0.23 | Likely Benign | 0.456 | Likely Benign | -0.75 | Neutral | 0.462 | Possibly Damaging | 0.693 | Possibly Damaging | 5.05 | Benign | 0.01 | Affected | 4.32 | 8 | 0.1844 | 0.5871 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||
| c.130T>G | W44G 2D  AIThe SynGAP1 missense variant W44G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (5) than benign (3), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -4.658 | Likely Benign | 0.850 | Likely Pathogenic | Ambiguous | 0.323 | Likely Benign | -4.80 | Deleterious | 0.659 | Possibly Damaging | 0.693 | Possibly Damaging | 3.16 | Benign | 0.00 | Affected | 0.4198 | 0.2164 | -7 | -2 | 0.5 | -129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.131G>T | W44L 2D  AIThe SynGAP1 missense variant W44L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard predictors shows a split: benign calls come from REVEL, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessment is inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a pathogenic interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -5.743 | Likely Benign | 0.869 | Likely Pathogenic | Ambiguous | 0.211 | Likely Benign | -4.37 | Deleterious | 0.659 | Possibly Damaging | 0.693 | Possibly Damaging | 3.20 | Benign | 0.00 | Affected | 0.2584 | 0.3413 | -2 | -2 | 4.7 | -73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.154T>C | S52P 2D AIThe SynGAP1 missense variant S52P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes); and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S52P. This conclusion does not contradict ClinVar, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -10.007 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -1.28 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.2276 | 0.5909 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2638G>C | A880P 2D AIThe SynGAP1 missense variant A880P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -3.671 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.55 | Neutral | 0.971 | Probably Damaging | 0.693 | Possibly Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.1744 | 0.4106 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.1588A>C | K530Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K530Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (13/16) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -10.593 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.31 | Likely Benign | 0.0 | 0.87 | Ambiguous | 0.59 | Ambiguous | 0.13 | Likely Benign | 0.524 | Likely Pathogenic | -3.18 | Deleterious | 0.698 | Possibly Damaging | 0.694 | Possibly Damaging | -1.61 | Pathogenic | 0.01 | Affected | 0.3001 | 0.0941 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1870A>G | T624A 2D  AIThe SynGAP1 T624A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FoldX and Foldetta, while the majority of tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic outcome. Uncertain predictions come from AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect for T624A, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -12.967 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | -0.38 | Likely Benign | 0.4 | 0.51 | Ambiguous | 0.07 | Likely Benign | 0.80 | Ambiguous | 0.895 | Likely Pathogenic | -4.94 | Deleterious | 0.962 | Probably Damaging | 0.694 | Possibly Damaging | -1.45 | Pathogenic | 0.03 | Affected | 0.2903 | 0.2872 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.2053T>G | L685V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability methods provide definitive evidence. Overall, the preponderance of pathogenic predictions, including the SGM Consensus, suggests that the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -11.418 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.87 | Ambiguous | 0.0 | 1.15 | Ambiguous | 1.51 | Ambiguous | 0.97 | Ambiguous | 0.214 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.694 | Possibly Damaging | 3.33 | Benign | 0.02 | Affected | 0.1414 | 0.3010 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2083C>G | L695V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta is also unavailable. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -10.605 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 1.61 | Ambiguous | 0.0 | 1.57 | Ambiguous | 1.59 | Ambiguous | 1.19 | Destabilizing | 0.274 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.694 | Possibly Damaging | 3.20 | Benign | 0.02 | Affected | 0.1158 | 0.2828 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.556T>A | L186M 2D AIThe SynGAP1 missense variant L186M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (5 pathogenic vs. 3 benign) suggest a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.783 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -1.58 | Neutral | 0.952 | Possibly Damaging | 0.694 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.0671 | 0.3396 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.611C>A | S204Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive because it receives an equal split between pathogenic and benign calls. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -10.518 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 8.99 | Destabilizing | 3.8 | 5.20 | Destabilizing | 7.10 | Destabilizing | -0.03 | Likely Benign | 0.170 | Likely Benign | -0.96 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.0452 | 0.5625 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.611C>T | S204F 2D AIThe SynGAP1 missense variant S204F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and FATHMM, whereas a majority of tools (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with high‑accuracy tools supporting pathogenicity—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.693 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 7.35 | Destabilizing | 6.1 | 4.21 | Destabilizing | 5.78 | Destabilizing | -0.09 | Likely Benign | 0.161 | Likely Benign | -0.88 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.16 | Benign | 0.03 | Affected | 0.0468 | 0.5764 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.683C>G | T228R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T228R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -7.218 | In-Between | 0.965 | Likely Pathogenic | Likely Pathogenic | -0.23 | Likely Benign | 0.1 | 0.69 | Ambiguous | 0.23 | Likely Benign | 0.67 | Ambiguous | 0.693 | Likely Pathogenic | -3.40 | Deleterious | 0.952 | Possibly Damaging | 0.694 | Possibly Damaging | 5.60 | Benign | 0.01 | Affected | 0.1108 | 0.3405 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||
| c.146G>T | C49F 2D  AIThe SynGAP1 missense variant C49F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—classifies the variant as pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -7.194 | In-Between | 0.893 | Likely Pathogenic | Ambiguous | 0.301 | Likely Benign | -3.21 | Deleterious | 0.676 | Possibly Damaging | 0.695 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | 0.1199 | 0.3690 | -4 | -2 | 0.3 | 44.04 | ||||||||||||||||||||||||||||||||||||||||
| c.712G>A | E238K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238K missense change is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: a single benign call from FATHMM, and a consensus of pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are not considered evidence. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238K. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -13.475 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.56 | Ambiguous | 0.4 | 1.83 | Ambiguous | 1.20 | Ambiguous | 0.83 | Ambiguous | 0.858 | Likely Pathogenic | -3.63 | Deleterious | 0.995 | Probably Damaging | 0.695 | Possibly Damaging | 5.46 | Benign | 0.01 | Affected | 4.29 | 391 | 0.2812 | 0.5524 | 0 | 1 | -0.4 | -0.94 | 209.0 | 55.9 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Pathogenic | The negatively charged residue Glu238, located in an α helix (res. Ala236-Val250), is replaced by the positively charged residue Lys238. This charge reversal removes the periodically formed salt bridge between the carboxylate group of Glu238 and the guanidinium group of Arg234 observed in the WT simulations. In the variant simulations, both Lys238 and Arg234 form alternative salt bridges with the carboxylate group of Glu680 in the GAP domain loop. Although not visible in the simulations, the absence of the Glu238-Arg234 salt bridge could weaken the integrity of the α helix (residues Ala236-Val250) and potentially affect the tertiary assembly between the PH and GAP domains. | ||||||||||||||||||
| c.1996G>C | E666Q 2D AIThe SynGAP1 E666Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split and is treated as unavailable. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -10.963 | Likely Pathogenic | 0.737 | Likely Pathogenic | Likely Benign | 0.54 | Ambiguous | 0.5 | 0.20 | Likely Benign | 0.37 | Likely Benign | 0.46 | Likely Benign | 0.268 | Likely Benign | -2.29 | Neutral | 0.997 | Probably Damaging | 0.696 | Possibly Damaging | 3.46 | Benign | 0.13 | Tolerated | 0.1437 | 0.4788 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.3313C>T | R1105W 2D AIThe SynGAP1 missense variant R1105W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443865‑C‑T). Prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default tool remains uncertain. A consensus analysis (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1105W, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 1 | 6-33443865-C-T | 6 | 3.93e-6 | -6.911 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1154 | 0.4117 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2531T>G | L844R 2D  AIThe SynGAP1 missense variant L844R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | -9.355 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.267 | Likely Benign | -2.77 | Deleterious | 0.960 | Probably Damaging | 0.697 | Possibly Damaging | 2.60 | Benign | 0.01 | Affected | 0.1230 | 0.0947 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2545G>C | D849H 2D  AIThe SynGAP1 missense variant D849H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.554191 | Binding | 0.319 | 0.813 | 0.500 | -4.624 | Likely Benign | 0.345 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -0.52 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.1977 | 0.8673 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2554G>C | G852R 2D  AIThe SynGAP1 missense variant G852R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G852R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -5.507 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.31 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.16 | Benign | 0.01 | Affected | 0.0978 | 0.4446 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2555G>T | G852V 2D  AIThe SynGAP1 missense variant G852V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G852V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -5.629 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.30 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.19 | Benign | 0.02 | Affected | 0.1205 | 0.4173 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2593G>C | A865P 2D AIThe SynGAP1 missense variant A865P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -4.178 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.66 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 2.67 | Benign | 0.27 | Tolerated | 0.1707 | 0.4690 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2972G>A | G991E 2D  AIThe SynGAP1 missense variant G991E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -4.729 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.30 | Neutral | 0.846 | Possibly Damaging | 0.697 | Possibly Damaging | 4.13 | Benign | 0.01 | Affected | 0.1480 | 0.4277 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3385C>A | L1129M 2D AIThe SynGAP1 missense variant L1129M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for L1129M, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | -4.233 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.295 | Likely Benign | -0.59 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 5.43 | Benign | 0.00 | Affected | 0.1100 | 0.4236 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.11C>G | S4C 2D AIThe SynGAP1 missense variant S4C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for S4C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -5.210 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.106 | Likely Benign | 0.41 | Neutral | 0.880 | Possibly Damaging | 0.700 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.0976 | 0.6129 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.1613A>G | E538G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability result is definitive. Overall, the balance of evidence, including the majority‑vote SGM Consensus and the higher number of pathogenic predictions, points to a pathogenic effect for E538G. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -9.258 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.91 | Ambiguous | 0.0 | 1.07 | Ambiguous | 0.99 | Ambiguous | 0.31 | Likely Benign | 0.285 | Likely Benign | -5.10 | Deleterious | 0.993 | Probably Damaging | 0.700 | Possibly Damaging | 3.33 | Benign | 0.03 | Affected | 0.3173 | 0.3713 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1890C>G | I630M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I630M is listed in gnomAD (ID 6‑33440942‑C‑G) but has no ClinVar entry. Functional prediction tools show a split: benign calls come from Rosetta, Foldetta, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic calls come from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. FoldX is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. High‑accuracy assessments give AlphaMissense‑Optimized benign, Foldetta benign, and an inconclusive SGM Consensus. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.036106 | Uncertain | 0.966 | 0.236 | 0.000 | 6-33440942-C-G | 1 | 6.20e-7 | -10.586 | Likely Pathogenic | 0.259 | Likely Benign | Likely Benign | -0.55 | Ambiguous | 0.1 | 0.32 | Likely Benign | -0.12 | Likely Benign | 1.06 | Destabilizing | 0.508 | Likely Pathogenic | -1.90 | Neutral | 0.833 | Possibly Damaging | 0.700 | Possibly Damaging | -1.38 | Pathogenic | 0.02 | Affected | 3.37 | 34 | 0.0618 | 0.1759 | 1 | 2 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.260C>G | S87C 2D AIThe SynGAP1 missense variant S87C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is uncertain due to a 2‑to‑2 split; and Foldetta, which assesses protein‑folding stability, is unavailable for this variant. Overall, the majority of available predictions (five pathogenic versus three benign) indicate a likely pathogenic impact. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.550904 | Binding | 0.302 | 0.878 | 0.500 | -8.769 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | -2.14 | Neutral | 0.880 | Possibly Damaging | 0.700 | Possibly Damaging | 3.74 | Benign | 0.00 | Affected | 0.0794 | 0.4849 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3505G>C | E1169Q 2D AIThe SynGAP1 missense variant E1169Q is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444540‑G‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are made by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and no evidence from ClinVar contradicts this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | 6-33444540-G-C | 1 | 6.20e-7 | -3.096 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -1.27 | Neutral | 0.872 | Possibly Damaging | 0.701 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.88 | 3 | 0.0940 | 0.6392 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.1497A>C | R499S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is catalogued in gnomAD (ID 6‑33438529‑A‑C) but has no ClinVar entry. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool reports a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta are uncertain, whereas the SGM‑Consensus remains likely pathogenic. Protein‑stability predictions are inconclusive (FoldX uncertain, Rosetta pathogenic, Foldetta uncertain). Taken together, the overwhelming majority of evidence supports a pathogenic classification for R499S. This conclusion is consistent with the absence of a ClinVar status, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438529-A-C | 1 | 6.20e-7 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | 0.632 | Likely Pathogenic | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2443 | 0.1649 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||
| c.1497A>T | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta all predict pathogenicity, while FoldX, AlphaMissense‑Optimized, and Foldetta are uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta likewise yields an uncertain result. Taken together, the overwhelming majority of reliable tools predict a pathogenic effect, and there is no ClinVar annotation to contradict this assessment. Therefore, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | 0.632 | Likely Pathogenic | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2443 | 0.1649 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||
| c.1674C>A | H558Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H558Q is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify the variant as benign include SIFT, FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools report uncertainty: AlphaMissense‑Default and premPS. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing. Overall, the majority of tools lean toward pathogenicity, but the presence of several benign predictions and conflicting high‑accuracy outputs suggests uncertainty. The variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.011039 | Uncertain | 0.897 | 0.200 | 0.000 | -11.483 | Likely Pathogenic | 0.496 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.11 | Likely Benign | 0.97 | Ambiguous | 0.522 | Likely Pathogenic | -4.23 | Deleterious | 0.991 | Probably Damaging | 0.702 | Possibly Damaging | -1.25 | Pathogenic | 0.13 | Tolerated | 0.1182 | 0.2058 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1674C>G | H558Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H558Q is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify the variant as benign include SIFT, FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools report uncertainty: AlphaMissense‑Default and premPS. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing. Overall, the majority of tools lean toward pathogenicity, but the presence of several benign predictions and conflicting high‑accuracy outputs suggests uncertainty. The variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.011039 | Uncertain | 0.897 | 0.200 | 0.000 | -11.483 | Likely Pathogenic | 0.496 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.11 | Likely Benign | 0.97 | Ambiguous | 0.522 | Likely Pathogenic | -4.23 | Deleterious | 0.991 | Probably Damaging | 0.702 | Possibly Damaging | -1.25 | Pathogenic | 0.13 | Tolerated | 0.1182 | 0.2058 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.2524T>A | S842T 2D  AIThe SynGAP1 missense variant S842T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy predictors) is Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S842T, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | -13.443 | Likely Pathogenic | 0.725 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -2.23 | Neutral | 0.983 | Probably Damaging | 0.702 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.0974 | 0.5391 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2929G>T | A977S 2D AIThe SynGAP1 missense variant A977S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence indicates that A977S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.909 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.38 | Neutral | 0.965 | Probably Damaging | 0.702 | Possibly Damaging | 4.02 | Benign | 0.45 | Tolerated | 0.2820 | 0.5373 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2930C>G | A977G 2D  AIThe SynGAP1 missense variant A977G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A977G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -3.250 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.79 | Neutral | 0.965 | Probably Damaging | 0.702 | Possibly Damaging | 4.03 | Benign | 0.05 | Affected | 0.2180 | 0.4408 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.728T>C | I243T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as pathogenic. Only FATHMM predicts a benign outcome, while Foldetta, AlphaMissense‑Optimized, and Rosetta return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that I243T is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -9.102 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 2.15 | Destabilizing | 0.2 | 1.52 | Ambiguous | 1.84 | Ambiguous | 1.72 | Destabilizing | 0.816 | Likely Pathogenic | -3.06 | Deleterious | 0.982 | Probably Damaging | 0.702 | Possibly Damaging | 5.55 | Benign | 0.01 | Affected | 0.1027 | 0.0541 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1590G>C | K530N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K530N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (10/13) support pathogenicity, with only three tools indicating benign. Therefore, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -12.459 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.33 | Likely Benign | 0.56 | Ambiguous | 0.553 | Likely Pathogenic | -4.18 | Deleterious | 0.950 | Possibly Damaging | 0.703 | Possibly Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.2350 | 0.1086 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1590G>T | K530N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (10/13) support pathogenicity, with only three tools indicating benign. Therefore, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -12.459 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.33 | Likely Benign | 0.56 | Ambiguous | 0.553 | Likely Pathogenic | -4.18 | Deleterious | 0.950 | Possibly Damaging | 0.703 | Possibly Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.2350 | 0.1086 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.207C>G | I69M 2D AIThe SynGAP1 missense variant I69M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for I69M, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.466129 | Uncertain | 0.437 | 0.786 | 0.375 | -4.071 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.29 | Neutral | 0.943 | Possibly Damaging | 0.703 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.0579 | 0.2906 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2726T>G | M909R 2D AIThe SynGAP1 missense variant M909R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.064 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.127 | Likely Benign | -1.23 | Neutral | 0.965 | Probably Damaging | 0.703 | Possibly Damaging | 2.70 | Benign | 0.12 | Tolerated | 0.1745 | 0.0809 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3410A>C | H1137P 2D  AIThe SynGAP1 missense variant H1137P is listed in ClinVar as a benign alteration (ClinVar ID 3685596.0) and is present in the gnomAD database (gnomAD ID 6‑33444445‑A‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same four high‑accuracy predictors) also indicates benign. No Foldetta (FoldX‑MD/Rosetta stability) result is available for this variant. Overall, the majority of predictions, including the most reliable tools, support a benign classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | Benign | 1 | 6-33444445-A-C | 12 | 7.44e-6 | -2.098 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.419 | Likely Benign | -1.93 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.29 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2045 | 0.4501 | -2 | 0 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||
| c.3411T>A | H1137Q 2D AIThe SynGAP1 missense variant H1137Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -2.958 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.239 | Likely Benign | -1.19 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.34 | Benign | 0.00 | Affected | 0.1873 | 0.4090 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3411T>G | H1137Q 2D AIThe SynGAP1 missense variant H1137Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H1137Q, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -2.958 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.239 | Likely Benign | -1.19 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.34 | Benign | 0.00 | Affected | 0.1873 | 0.4090 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3521A>T | E1174V 2D  AIThe SynGAP1 missense variant E1174V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from PROVEAN, ESM1b, and FATHMM, while pathogenic calls are made by REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Grouping by consensus, the majority of tools (four out of six) predict a benign effect, whereas the remaining four predict pathogenicity. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence leans toward a benign impact for E1174V, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -4.814 | Likely Benign | 0.877 | Likely Pathogenic | Ambiguous | 0.515 | Likely Pathogenic | -2.41 | Neutral | 0.965 | Probably Damaging | 0.703 | Possibly Damaging | 5.41 | Benign | 0.01 | Affected | 0.0539 | 0.6623 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.1147G>T | G383W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G383W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438052‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta as pathogenic. Because the majority of conventional predictors favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic interpretation. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | Uncertain | 1 | 6-33438052-G-T | 1 | 6.22e-7 | -10.161 | Likely Pathogenic | 0.439 | Ambiguous | Likely Benign | 5.81 | Destabilizing | 3.6 | 4.44 | Destabilizing | 5.13 | Destabilizing | 0.08 | Likely Benign | 0.469 | Likely Benign | -1.01 | Neutral | 0.959 | Probably Damaging | 0.704 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 4.32 | 7 | 0.0972 | 0.3785 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||
| c.2705C>T | A902V 2D  AIThe SynGAP1 missense variant A902V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A902V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -4.768 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.15 | Neutral | 0.983 | Probably Damaging | 0.704 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 0.1124 | 0.6602 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.710C>A | A237D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. Two tools, FoldX and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the evidence overwhelmingly indicates that the variant is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.880 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 1.23 | Ambiguous | 0.4 | 3.49 | Destabilizing | 2.36 | Destabilizing | 1.20 | Destabilizing | 0.769 | Likely Pathogenic | -3.97 | Deleterious | 0.969 | Probably Damaging | 0.704 | Possibly Damaging | 5.88 | Benign | 0.05 | Affected | 0.1419 | 0.2302 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.722A>T | K241I 2D  3DClick to see structure in 3D Viewer AISynGAP1 K241I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, and FATHMM. Those that predict a damaging effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta return uncertain results. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -14.370 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.5 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.41 | Likely Benign | 0.852 | Likely Pathogenic | -6.96 | Deleterious | 0.985 | Probably Damaging | 0.704 | Possibly Damaging | 5.71 | Benign | 0.01 | Affected | 0.1176 | 0.3868 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1154C>T | S385L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438059‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus itself is benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of computational evidence indicates the variant is most likely benign, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | Uncertain | 2 | 6-33438059-C-T | 9 | 4.60e-5 | -6.018 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.12 | Likely Benign | -0.26 | Likely Benign | 0.304 | Likely Benign | -0.68 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.63 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1897 | 0.6244 | -3 | -2 | 4.6 | 26.08 | 244.6 | -50.1 | 0.0 | 0.6 | -0.1 | 0.1 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| c.1526C>G | A509G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that clearly indicate benign effect include only AlphaMissense‑Optimized. All other evaluated tools that provide a definitive call predict pathogenicity: SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Tools with inconclusive results (AlphaMissense‑Default, FoldX, and Foldetta) are treated as unavailable and do not influence the overall assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, combining FoldX‑MD (uncertain) and Rosetta (pathogenic), is uncertain. Overall, the majority of definitive predictions support a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -11.873 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 1.36 | Ambiguous | 0.2 | 2.33 | Destabilizing | 1.85 | Ambiguous | 1.14 | Destabilizing | 0.804 | Likely Pathogenic | -3.57 | Deleterious | 0.911 | Possibly Damaging | 0.706 | Possibly Damaging | -1.39 | Pathogenic | 0.00 | Affected | 0.2193 | 0.4213 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1534G>C | E512Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512Q missense change is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Because the variant is absent from ClinVar and gnomAD, there is no external evidence to contradict the computational predictions. Overall, the balance of high‑confidence tools leans toward a pathogenic interpretation, though the presence of an equal number of benign predictions indicates that the evidence remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -9.964 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 0.09 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.26 | Likely Benign | 0.00 | Likely Benign | 0.283 | Likely Benign | -2.86 | Deleterious | 0.947 | Possibly Damaging | 0.706 | Possibly Damaging | 3.32 | Benign | 0.14 | Tolerated | 0.1523 | 0.4815 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.155C>T | S52L 2D AISynGAP1 missense variant S52L is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33423564‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the collective evidence points to a likely benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | Uncertain | 1 | 6-33423564-C-T | 1 | 6.20e-7 | -7.199 | In-Between | 0.688 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.41 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0991 | 0.6100 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||
| c.568A>T | S190C 2D AIThe SynGAP1 missense variant S190C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.696 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.04 | Neutral | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 4.01 | Benign | 0.23 | Tolerated | 0.0937 | 0.6667 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.692T>G | F231C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.315 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.3 | 2.82 | Destabilizing | 2.54 | Destabilizing | 2.04 | Destabilizing | 0.937 | Likely Pathogenic | -6.89 | Deleterious | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.2527 | 0.1612 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.2389C>A | P797T 2D  AIThe SynGAP1 missense variant P797T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.926919 | Disordered | 0.449970 | Uncertain | 0.561 | 0.902 | 0.875 | -6.554 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.15 | Neutral | 0.901 | Possibly Damaging | 0.708 | Possibly Damaging | 4.23 | Benign | 0.24 | Tolerated | 0.1733 | 0.5830 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2951A>C | K984T 2D  AIThe SynGAP1 missense variant K984T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the predictions are mixed; however, the SGM‑Consensus and the majority of benign‑predicting tools lean toward a benign interpretation. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -3.429 | Likely Benign | 0.854 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.10 | Neutral | 0.951 | Possibly Damaging | 0.708 | Possibly Damaging | 2.71 | Benign | 0.00 | Affected | 0.2441 | 0.3463 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3002T>G | L1001R 2D AIThe SynGAP1 missense variant L1001R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -2.285 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.09 | Neutral | 0.966 | Probably Damaging | 0.708 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1299 | 0.0832 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.307G>C | G103R 2D AIThe SynGAP1 missense variant G103R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.384 | Likely Benign | 0.710 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | 0.00 | Neutral | 0.949 | Possibly Damaging | 0.708 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 0.1198 | 0.4362 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.1949A>C | N650T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.626 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.52 | Ambiguous | 0.69 | Ambiguous | 0.471 | Likely Benign | -5.98 | Deleterious | 0.986 | Probably Damaging | 0.710 | Possibly Damaging | 3.04 | Benign | 0.01 | Affected | 0.1700 | 0.4843 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.2024A>C | N675T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. No evidence contradicts the ClinVar status. Overall, the balance of evidence, especially from the high‑accuracy tools, indicates that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -10.636 | Likely Pathogenic | 0.208 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.3 | -0.67 | Ambiguous | -0.16 | Likely Benign | 0.56 | Ambiguous | 0.258 | Likely Benign | -4.63 | Deleterious | 0.991 | Probably Damaging | 0.710 | Possibly Damaging | 3.49 | Benign | 0.05 | Affected | 0.1283 | 0.7910 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.3049T>A | F1017I 2D  AIThe SynGAP1 missense variant F1017I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of conventional tools (5 pathogenic vs 4 benign) lean toward pathogenicity, but the single high‑accuracy benign prediction introduces uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -3.244 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.55 | Deleterious | 0.951 | Possibly Damaging | 0.710 | Possibly Damaging | 2.50 | Benign | 0.05 | Affected | 0.2050 | 0.1969 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.197C>T | P66L 2D  AIThe SynGAP1 missense variant P66L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized calling the variant pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are not available. Overall, the predictions are split evenly between benign and pathogenic, with high‑accuracy tools providing opposing conclusions. Consequently, the variant’s impact remains uncertain and does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -2.437 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.194 | Likely Benign | -2.48 | Neutral | 0.909 | Possibly Damaging | 0.713 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.2412 | 0.6687 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2998A>T | I1000F 2D  AIThe SynGAP1 missense variant I1000F is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions indicates that I1000F is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -3.801 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -1.02 | Neutral | 0.968 | Probably Damaging | 0.713 | Possibly Damaging | 2.70 | Benign | 0.13 | Tolerated | 0.0594 | 0.3259 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3697A>T | I1233F 2D AIThe SynGAP1 missense variant I1233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, more tools predict pathogenicity (five) than benignity (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -8.414 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -2.34 | Neutral | 0.968 | Probably Damaging | 0.713 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 0.0418 | 0.2731 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.59C>T | P20L 2D AIThe SynGAP1 missense variant P20L (ClinVar ID 1185912.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | Uncertain | 3 | -3.289 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.100 | Likely Benign | -0.44 | Neutral | 0.909 | Possibly Damaging | 0.713 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2479 | 0.7258 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.1896C>A | N632K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632K is not reported in ClinVar and is present in gnomAD. Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify it as pathogenic; premPS is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the preponderance of evidence points to a pathogenic effect for N632K, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | 6-33440948-C-A | -13.266 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.12 | Likely Benign | 0.03 | Likely Benign | 0.95 | Ambiguous | 0.766 | Likely Pathogenic | -5.14 | Deleterious | 0.983 | Probably Damaging | 0.714 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.2375 | 0.4897 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1896C>G | N632K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -13.266 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.12 | Likely Benign | 0.03 | Likely Benign | 0.95 | Ambiguous | 0.766 | Likely Pathogenic | -5.14 | Deleterious | 0.983 | Probably Damaging | 0.714 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.2375 | 0.4897 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.574G>A | A192T 2D AIThe SynGAP1 missense variant A192T has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.562 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -2.46 | Neutral | 0.978 | Probably Damaging | 0.714 | Possibly Damaging | 3.96 | Benign | 0.34 | Tolerated | 0.1148 | 0.5343 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2958G>C | E986D 2D  AIThe SynGAP1 missense variant E986D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign votes) and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. There is no contradiction with ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.001 | Likely Benign | 0.628 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.2081 | 0.5364 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2958G>T | E986D 2D AIThe SynGAP1 missense variant E986D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign votes) and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. There is no contradiction with ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.001 | Likely Benign | 0.628 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.2081 | 0.5364 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3728A>C | Q1243P 2D  AIThe SynGAP1 missense variant Q1243P has no ClinVar record and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. With five tools favoring pathogenicity versus three favoring benign, the overall evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Thus, based on the available predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -12.872 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -2.31 | Neutral | 0.969 | Probably Damaging | 0.715 | Possibly Damaging | 2.65 | Benign | 0.05 | Affected | 0.1624 | 0.3607 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.699T>G | C233W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.899 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | 0.772 | Likely Pathogenic | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 0.1727 | 0.5292 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.743G>A | R248Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248Q is catalogued in gnomAD (ID 6‑33435594‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, whereas pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R248Q, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | 6-33435594-G-A | 2 | 1.24e-6 | -10.573 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.45 | Likely Benign | 0.2 | 1.67 | Ambiguous | 1.06 | Ambiguous | 1.05 | Destabilizing | 0.739 | Likely Pathogenic | -3.34 | Deleterious | 0.999 | Probably Damaging | 0.715 | Possibly Damaging | 5.74 | Benign | 0.01 | Affected | 3.41 | 14 | 0.2572 | 0.2549 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.1996G>A | E666K 2D AIThe SynGAP1 missense variant E666K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -11.367 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.20 | Likely Benign | 0.6 | 0.30 | Likely Benign | 0.25 | Likely Benign | 0.43 | Likely Benign | 0.401 | Likely Benign | -3.26 | Deleterious | 0.992 | Probably Damaging | 0.717 | Possibly Damaging | 3.46 | Benign | 0.05 | Affected | 0.2953 | 0.5300 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.337G>T | G113W 2D AIThe SynGAP1 missense variant G113W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence (six benign versus four pathogenic predictions) supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -5.635 | Likely Benign | 0.620 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -2.44 | Neutral | 0.983 | Probably Damaging | 0.717 | Possibly Damaging | 4.10 | Benign | 0.01 | Affected | 0.0700 | 0.4462 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.1480A>C | I494L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence (five pathogenic versus four benign predictions, with several uncertain calls) leans toward a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | 0.513 | Likely Pathogenic | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 0.0816 | 0.2851 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1480A>T | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta indicating uncertain stability change. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools and the SGM Consensus supporting a deleterious effect. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | 0.513 | Likely Pathogenic | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 0.0816 | 0.2851 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1804A>C | I602L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Three tools (Rosetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the balance of evidence leans toward pathogenicity, with no conflict with the ClinVar status because the variant is not yet classified in that database. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -9.660 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | -0.15 | Likely Benign | 0.1 | 1.12 | Ambiguous | 0.49 | Likely Benign | 0.91 | Ambiguous | 0.631 | Likely Pathogenic | -1.99 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -1.54 | Pathogenic | 0.04 | Affected | 0.1044 | 0.3199 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1142G>A | G381E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. With seven pathogenic versus four benign predictions and two high‑accuracy tools supporting pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | -9.360 | Likely Pathogenic | 0.540 | Ambiguous | Likely Benign | 5.52 | Destabilizing | 1.1 | 0.53 | Ambiguous | 3.03 | Destabilizing | 0.24 | Likely Benign | 0.588 | Likely Pathogenic | -0.71 | Neutral | 0.985 | Probably Damaging | 0.720 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1554 | 0.3735 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1157G>T | G386V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386V is reported in gnomAD (6-33438062‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign classification, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | 6-33438062-G-T | -6.405 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 4.88 | Destabilizing | 3.0 | 5.09 | Destabilizing | 4.99 | Destabilizing | -0.17 | Likely Benign | 0.458 | Likely Benign | -0.64 | Neutral | 0.985 | Probably Damaging | 0.720 | Possibly Damaging | 3.91 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1685 | 0.4189 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.2210A>T | Q737L 2D  AIThe SynGAP1 missense variant Q737L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -2.789 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.44 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.80 | Benign | 1.00 | Tolerated | 0.0958 | 0.5494 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2306T>A | L769H 2D AIThe SynGAP1 missense variant L769H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which classify the variant as benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, all of which report the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.038 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.235 | Likely Benign | -1.96 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1016 | 0.0828 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2566A>G | N856D 2D AIThe SynGAP1 missense variant N856D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and consensus analyses indicates that the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.477615 | Uncertain | 0.263 | 0.827 | 0.500 | -4.636 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.25 | Neutral | 0.965 | Probably Damaging | 0.721 | Possibly Damaging | 4.17 | Benign | 0.61 | Tolerated | 0.1875 | 0.4895 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2568C>A | N856K 2D AIThe SynGAP1 missense variant N856K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. Overall, the preponderance of evidence points to a benign effect for N856K, and this conclusion is not in conflict with any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.477615 | Uncertain | 0.263 | 0.827 | 0.500 | -3.511 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.51 | Neutral | 0.965 | Probably Damaging | 0.721 | Possibly Damaging | 4.19 | Benign | 0.26 | Tolerated | 0.2065 | 0.6252 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2568C>G | N856K 2D AIThe SynGAP1 missense variant N856K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for N856K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.477615 | Uncertain | 0.263 | 0.827 | 0.500 | -3.511 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.51 | Neutral | 0.965 | Probably Damaging | 0.721 | Possibly Damaging | 4.19 | Benign | 0.26 | Tolerated | 0.2065 | 0.6252 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2731G>T | V911F 2D  AIThe SynGAP1 missense variant V911F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for V911F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -4.454 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.08 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.68 | Benign | 0.04 | Affected | 0.0749 | 0.4380 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2752G>A | A918T 2D AISynGAP1 missense variant A918T is listed in ClinVar with an uncertain significance (ClinVar ID 3964538.0) and is present in gnomAD (6‑33443304‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 1 | 6-33443304-G-A | 1 | 6.20e-7 | -4.139 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.09 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1742 | 0.6430 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2753C>A | A918D 2D AIThe SynGAP1 missense variant A918D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -4.281 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.99 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.2037 | 0.2412 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2769C>G | I923M 2D AIThe SynGAP1 missense variant I923M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that I923M is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.964857 | Binding | 0.292 | 0.852 | 0.250 | -2.711 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.14 | Neutral | 0.973 | Probably Damaging | 0.721 | Possibly Damaging | 2.70 | Benign | 0.16 | Tolerated | 0.0949 | 0.3874 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>A | S955Y 2D AIThe SynGAP1 missense variant S955Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -6.212 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.62 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.1321 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>T | S955F 2D AISynGAP1 missense variant S955F is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33443416‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions favor a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | Conflicting | 4 | 6-33443416-C-T | 95 | 5.89e-5 | -7.374 | In-Between | 0.176 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.73 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1246 | 0.4943 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||
| c.3026A>G | E1009G 2D AIThe SynGAP1 missense variant E1009G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; Foldetta results are unavailable. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -2.758 | Likely Benign | 0.610 | Likely Pathogenic | Likely Benign | 0.123 | Likely Benign | -3.06 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.36 | Pathogenic | 0.01 | Affected | 0.2800 | 0.6003 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3028T>G | F1010V 2D  AIThe SynGAP1 missense variant F1010V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the balance of evidence from multiple independent predictors and the consensus analysis points to a benign classification for F1010V, with no conflict with ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -2.482 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.10 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.58 | Benign | 0.03 | Affected | 0.2351 | 0.2403 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3111C>G | I1037M 2D AIThe SynGAP1 missense variant I1037M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -3.849 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.40 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.71 | Benign | 0.18 | Tolerated | 0.0775 | 0.3885 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3117T>G | I1039M 2D AIThe SynGAP1 missense variant I1039M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for I1039M, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -3.444 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.38 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.68 | Benign | 0.16 | Tolerated | 0.0926 | 0.4392 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3202T>A | L1068M 2D AIThe SynGAP1 missense variant L1068M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -5.739 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.22 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.0930 | 0.4582 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3638A>C | N1213T 2D AIThe SynGAP1 missense variant N1213T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446630‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0968 | 0.4546 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||
| c.3683A>G | E1228G 2D AIThe SynGAP1 E1228G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show one benign call (AlphaMissense‑Optimized) and no decisive pathogenic evidence. Overall, the majority of standard tools (5 pathogenic vs 4 benign) indicate a pathogenic likelihood, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -6.273 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.249 | Likely Benign | -4.54 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.2598 | 0.4030 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3736A>C | K1246Q 2D AIThe SynGAP1 missense change K1246Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that K1246Q is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -0.718 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.43 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.66 | Benign | 0.06 | Tolerated | 0.3708 | 0.0740 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3738G>C | K1246N 2D AIThe SynGAP1 missense variant K1246N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for K1246N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.506 | Likely Benign | 0.518 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -1.39 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | 0.3316 | 0.0940 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3738G>T | K1246N 2D AIThe SynGAP1 missense variant K1246N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for K1246N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.506 | Likely Benign | 0.518 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.39 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | 0.3316 | 0.0940 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3739A>G | R1247G 2D  AIThe SynGAP1 missense variant R1247G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; ESM1b is uncertain and SGM‑Consensus is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.736850 | Disordered | 0.374141 | Uncertain | 0.875 | 0.557 | 0.625 | -7.920 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 0.195 | Likely Benign | -5.58 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 1.70 | Pathogenic | 0.00 | Affected | 0.3047 | 0.2327 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3741G>C | R1247S 2D AIThe SynGAP1 missense variant R1247S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta data are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1247S. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.736850 | Disordered | 0.374141 | Uncertain | 0.875 | 0.557 | 0.625 | -6.935 | Likely Benign | 0.851 | Likely Pathogenic | Ambiguous | 0.209 | Likely Benign | -4.79 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.2802 | 0.1977 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3741G>T | R1247S 2D AIThe SynGAP1 missense variant R1247S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta data are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1247S. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.736850 | Disordered | 0.374141 | Uncertain | 0.875 | 0.557 | 0.625 | -6.935 | Likely Benign | 0.851 | Likely Pathogenic | Ambiguous | 0.209 | Likely Benign | -4.79 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.2802 | 0.1977 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.4001A>T | N1334I 2D  AIThe SynGAP1 missense variant N1334I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the balance of evidence (seven pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -5.880 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.193 | Likely Benign | -5.06 | Deleterious | 0.985 | Probably Damaging | 0.721 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.0861 | 0.5491 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.826C>A | P276T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, two pathogenic), and Foldetta is uncertain. Overall, the majority of tools (six pathogenic vs. four benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | -5.793 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 2.61 | Destabilizing | 0.1 | 0.75 | Ambiguous | 1.68 | Ambiguous | 0.63 | Ambiguous | 0.293 | Likely Benign | -3.53 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 1.87 | Pathogenic | 0.03 | Affected | 0.1601 | 0.4676 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.988G>A | D330N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D330N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” while AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No folding‑stability methods (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the preponderance of pathogenic predictions strongly suggests that D330N is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -12.993 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 1.61 | Ambiguous | 0.2 | 0.59 | Ambiguous | 1.10 | Ambiguous | 0.59 | Ambiguous | 0.350 | Likely Benign | -3.46 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 1.01 | Pathogenic | 0.02 | Affected | 0.1252 | 0.4263 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.2956G>A | E986K 2D AIThe SynGAP1 missense variant E986K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and PROVEAN, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results and are not considered evidence for either side. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic verdict (2 pathogenic vs. 1 benign, with one uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors classify the variant as pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -7.174 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -2.19 | Neutral | 0.924 | Possibly Damaging | 0.722 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.2760 | 0.7973 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.3206A>C | Q1069P 2D AIThe SynGAP1 missense variant Q1069P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -3.458 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.211 | Likely Benign | 0.75 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 2.73 | Benign | 1.00 | Tolerated | 0.2179 | 0.5944 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>T | V1078F 2D AIThe SynGAP1 missense variant V1078F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for V1078F, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.768 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -0.97 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 3.87 | Benign | 0.02 | Affected | 0.0677 | 0.4561 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3266G>T | G1089V 2D AIThe SynGAP1 missense variant G1089V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for G1089V. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -4.809 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.182 | Likely Benign | -2.81 | Deleterious | 0.984 | Probably Damaging | 0.722 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.1326 | 0.4413 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3851T>C | L1284P 2D AIThe SynGAP1 missense variant L1284P is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (ID 6‑33447899‑T‑C). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. Foldetta results are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation (five pathogenic versus four benign predictions). This assessment does not conflict with ClinVar, as the variant has no ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | 6-33447899-T-C | -2.451 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -3.05 | Deleterious | 0.990 | Probably Damaging | 0.722 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3307 | 0.0848 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||
| c.3851T>G | L1284R 2D AIThe SynGAP1 missense variant L1284R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.203 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -3.11 | Deleterious | 0.990 | Probably Damaging | 0.722 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1216 | 0.0488 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3046G>A | D1016N 2D AIThe SynGAP1 missense variant D1016N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments therefore indicate a benign prediction: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and no Foldetta data is available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.674 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.123 | Likely Benign | -2.12 | Neutral | 0.856 | Possibly Damaging | 0.723 | Possibly Damaging | 2.50 | Benign | 0.01 | Affected | 0.1989 | 0.7529 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3421C>A | P1141T 2D AIThe SynGAP1 missense variant P1141T is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic). High‑accuracy methods give AlphaMissense‑Optimized a benign prediction; the SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the balance of evidence, particularly the benign call from the high‑accuracy AlphaMissense‑Optimized model, suggests that the variant is most likely benign, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.090 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -3.85 | Deleterious | 0.856 | Possibly Damaging | 0.723 | Possibly Damaging | 0.98 | Pathogenic | 0.00 | Affected | 0.1594 | 0.6145 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.460A>C | S154R 2D  AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (five pathogenic vs four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.462C>A | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.462C>G | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.1193C>A | P398Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P398Q has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -7.402 | In-Between | 0.792 | Likely Pathogenic | Ambiguous | 2.13 | Destabilizing | 0.1 | 2.01 | Destabilizing | 2.07 | Destabilizing | 1.01 | Destabilizing | 0.719 | Likely Pathogenic | -5.57 | Deleterious | 0.996 | Probably Damaging | 0.724 | Possibly Damaging | 5.48 | Benign | 0.00 | Affected | 0.1522 | 0.5176 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||
| c.1193C>G | P398R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P398R variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—indicate a pathogenic effect, while Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -9.575 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 3.01 | Destabilizing | 0.5 | 1.35 | Ambiguous | 2.18 | Destabilizing | 0.98 | Ambiguous | 0.755 | Likely Pathogenic | -6.55 | Deleterious | 0.988 | Probably Damaging | 0.724 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.1479 | 0.3472 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.716G>T | R239I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -19.414 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.5 | 2.53 | Destabilizing | 3.43 | Destabilizing | 0.83 | Ambiguous | 0.890 | Likely Pathogenic | -7.16 | Deleterious | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.69 | Benign | 0.00 | Affected | 0.1480 | 0.3985 | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||
| c.727A>T | I243F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 3 benign) indicate a likely pathogenic impact. This assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -12.559 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 2.92 | Destabilizing | 2.5 | 0.53 | Ambiguous | 1.73 | Ambiguous | 0.42 | Likely Benign | 0.793 | Likely Pathogenic | -2.21 | Neutral | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.53 | Benign | 0.02 | Affected | 0.0409 | 0.2205 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||
| c.457A>C | T153P 2D AIThe SynGAP1 missense variant T153P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign interpretation. This conclusion does not conflict with ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -7.092 | In-Between | 0.374 | Ambiguous | Likely Benign | 0.269 | Likely Benign | -1.67 | Neutral | 0.983 | Probably Damaging | 0.725 | Possibly Damaging | 4.09 | Benign | 0.03 | Affected | 0.2270 | 0.3660 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.458C>T | T153I 2D AIThe SynGAP1 missense variant T153I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that predict a pathogenic effect comprise polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -8.809 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.00 | Neutral | 0.983 | Probably Damaging | 0.725 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 0.0839 | 0.4571 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||||||
| c.208C>G | R70G 2D AIThe SynGAP1 missense variant R70G is listed in gnomAD (ID 6‑33425816‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also indicates a likely benign outcome; Foldetta data are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.458981 | Uncertain | 0.392 | 0.793 | 0.375 | 6-33425816-C-G | 1 | 6.20e-7 | -3.555 | Likely Benign | 0.430 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -0.61 | Neutral | 0.962 | Probably Damaging | 0.726 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3078 | 0.3194 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||
| c.209G>T | R70L 2D AIThe SynGAP1 missense variant R70L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.458981 | Uncertain | 0.392 | 0.793 | 0.375 | -3.422 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -1.39 | Neutral | 0.962 | Probably Damaging | 0.726 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.1455 | 0.4554 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.250C>A | R84S 2D AIThe SynGAP1 missense variant R84S is not reported in ClinVar and has no gnomAD entry. Prediction tools show mixed results: benign predictions come from SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this discordance: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta stability analysis is unavailable. Overall, the majority of tools lean toward a benign interpretation, but a substantial subset predicts pathogenicity, leaving the variant’s effect uncertain. Based on the current predictions, R84S is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.529205 | Binding | 0.298 | 0.888 | 0.500 | -6.233 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.103 | Likely Benign | -2.18 | Neutral | 0.962 | Probably Damaging | 0.726 | Possibly Damaging | 3.71 | Benign | 0.00 | Affected | 0.2966 | 0.4139 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.250C>G | R84G 2D AIThe SynGAP1 missense variant R84G is listed in ClinVar with an “Uncertain” significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the majority of available predictions, the variant is most likely pathogenic, which does not contradict the current ClinVar status of “Uncertain.” Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.529205 | Binding | 0.298 | 0.888 | 0.500 | Uncertain | 1 | -6.627 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.139 | Likely Benign | -2.64 | Deleterious | 0.962 | Probably Damaging | 0.726 | Possibly Damaging | 3.68 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3387 | 0.3391 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| c.251G>T | R84L 2D AIThe SynGAP1 missense variant R84L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that R84L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.529205 | Binding | 0.298 | 0.888 | 0.500 | -7.579 | In-Between | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | -2.75 | Deleterious | 0.962 | Probably Damaging | 0.726 | Possibly Damaging | 3.70 | Benign | 0.00 | Affected | 0.1595 | 0.4653 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2933C>A | P978Q 2D AIThe SynGAP1 missense variant P978Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.975775 | Binding | 0.425 | 0.892 | 0.625 | -4.741 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.72 | Neutral | 0.990 | Probably Damaging | 0.726 | Possibly Damaging | 4.15 | Benign | 0.01 | Affected | 0.1651 | 0.5699 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2933C>G | P978R 2D AIThe SynGAP1 missense variant P978R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which classify the variant as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that P978R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.975775 | Binding | 0.425 | 0.892 | 0.625 | -2.852 | Likely Benign | 0.487 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -2.10 | Neutral | 0.970 | Probably Damaging | 0.726 | Possibly Damaging | 4.15 | Benign | 0.01 | Affected | 0.1530 | 0.4590 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3080A>T | N1027I 2D AIThe SynGAP1 missense variant N1027I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.847 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | -2.36 | Neutral | 0.970 | Probably Damaging | 0.726 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | 0.0677 | 0.5724 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3905T>C | L1302S 2D AIThe SynGAP1 missense variant L1302S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -3.411 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -4.17 | Deleterious | 0.960 | Probably Damaging | 0.726 | Possibly Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.3237 | 0.0982 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.271G>C | E91Q 2D AIThe SynGAP1 missense variant E91Q has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Overall, the predictions are mixed, with an equal number of benign and pathogenic calls, but the consensus‑based SGM‑Consensus and the majority of individual benign predictions lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | -4.053 | Likely Benign | 0.805 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.89 | Neutral | 0.947 | Possibly Damaging | 0.727 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 0.1487 | 0.7442 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.272A>G | E91G 2D AIThe SynGAP1 missense variant E91G is listed in ClinVar (ID 436922.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicating a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | Likely Benign | 1 | -3.226 | Likely Benign | 0.783 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -2.18 | Neutral | 0.947 | Possibly Damaging | 0.727 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3418 | 0.6030 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.290A>G | E97G 2D AIThe SynGAP1 missense variant E97G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.609018 | Binding | 0.340 | 0.867 | 0.625 | -2.752 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.03 | Neutral | 0.947 | Possibly Damaging | 0.727 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.3286 | 0.6569 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.1569C>A | N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.276 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.17 | Likely Benign | 0.2 | -0.58 | Ambiguous | -0.38 | Likely Benign | 0.73 | Ambiguous | 0.607 | Likely Pathogenic | -5.35 | Deleterious | 0.972 | Probably Damaging | 0.728 | Possibly Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.1837 | 0.2866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1569C>G | N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.276 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.17 | Likely Benign | 0.2 | -0.58 | Ambiguous | -0.38 | Likely Benign | 0.73 | Ambiguous | 0.607 | Likely Pathogenic | -5.35 | Deleterious | 0.972 | Probably Damaging | 0.728 | Possibly Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.1837 | 0.2866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.3040G>C | G1014R 2D AIThe SynGAP1 missense variant G1014R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; however, the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -3.234 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.47 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.80 | Benign | 0.12 | Tolerated | 0.1044 | 0.4714 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3104C>G | P1035R 2D AIThe SynGAP1 missense variant P1035R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -4.534 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.119 | Likely Benign | 1.07 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.89 | Benign | 0.93 | Tolerated | 0.1424 | 0.4201 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3104C>T | P1035L 2D AIThe SynGAP1 missense variant P1035L is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -5.694 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | -2.11 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.70 | Benign | 0.21 | Tolerated | 0.2444 | 0.7354 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3142G>A | G1048R 2D AIThe SynGAP1 missense variant G1048R is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: pathogenic calls come from REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar, whereas benign calls are made by PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority, and AlphaMissense‑Optimized itself predicts benign. The SGM‑Consensus, which aggregates these four predictors, reports a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3142G>C | G1048R 2D AIThe SynGAP1 missense variant G1048R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | Uncertain | 1 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3163G>A | G1055R 2D AIThe SynGAP1 missense variant G1055R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -8.778 | Likely Pathogenic | 0.375 | Ambiguous | Likely Benign | 0.275 | Likely Benign | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | 0.1013 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3163G>C | G1055R 2D AIThe SynGAP1 missense variant G1055R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -8.778 | Likely Pathogenic | 0.375 | Ambiguous | Likely Benign | 0.275 | Likely Benign | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | 0.1013 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3179G>T | G1060V 2D AIThe SynGAP1 missense variant G1060V is listed in ClinVar as benign (ClinVar ID 1345112.0) and is observed in gnomAD (6‑33443731‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign, and AlphaMissense‑Optimized also reports a benign outcome. No Foldetta stability assessment is available for this variant. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | Benign | 1 | 6-33443731-G-T | 1 | 6.22e-7 | -6.966 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.369 | Likely Benign | -0.73 | Neutral | 0.986 | Probably Damaging | 0.728 | Possibly Damaging | 2.63 | Benign | 0.33 | Tolerated | 4.32 | 2 | 0.1453 | 0.3494 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||
| c.3211G>C | G1071R 2D AIThe SynGAP1 missense variant G1071R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta results are not provided and are therefore unavailable. Overall, more tools predict pathogenicity (5) than benignity (3), and no ClinVar entry contradicts this assessment. **The variant is most likely pathogenic based on the available predictions.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -3.052 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.135 | Likely Benign | -2.61 | Deleterious | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.06 | Benign | 0.00 | Affected | 0.0980 | 0.4482 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3212G>A | G1071D 2D  AIThe SynGAP1 missense variant G1071D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, with no conflict with ClinVar status (which has no entry). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -4.704 | Likely Benign | 0.866 | Likely Pathogenic | Ambiguous | 0.101 | Likely Benign | -1.92 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.05 | Benign | 0.01 | Affected | 0.1760 | 0.2175 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>G | T1077R 2D AIThe SynGAP1 missense variant T1077R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), which collectively classify the variant as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and no Foldetta stability assessment is available. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.109 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.121 | Likely Benign | -1.01 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.18 | Benign | 0.03 | Affected | 0.1028 | 0.3491 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3446C>G | P1149R 2D AIThe SynGAP1 missense variant P1149R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for P1149R, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -4.340 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -1.94 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.1525 | 0.3671 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3871C>A | L1291M 2D AIThe SynGAP1 missense variant L1291M is reported in gnomAD (ID 6‑33447919‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four benign predictors) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447919-C-A | -5.625 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.93 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.53 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0767 | 0.2973 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.2519G>C | S840T 2D AIThe SynGAP1 missense variant S840T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.611356 | Binding | 0.259 | 0.865 | 0.250 | -7.243 | In-Between | 0.583 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -2.30 | Neutral | 0.951 | Possibly Damaging | 0.729 | Possibly Damaging | 1.55 | Pathogenic | 0.00 | Affected | 0.1068 | 0.5494 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3127A>T | R1043W 2D AIThe SynGAP1 missense variant R1043W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction; Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -6.382 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.444 | Likely Benign | -3.43 | Deleterious | 0.971 | Probably Damaging | 0.729 | Possibly Damaging | 5.38 | Benign | 0.00 | Affected | 0.1403 | 0.3696 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2057G>C | G686A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized and a Likely Pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -9.975 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.39 | Likely Benign | 0.2 | -0.46 | Likely Benign | -0.43 | Likely Benign | 0.58 | Ambiguous | 0.321 | Likely Benign | -5.19 | Deleterious | 0.993 | Probably Damaging | 0.732 | Possibly Damaging | 3.37 | Benign | 0.13 | Tolerated | 0.3744 | 0.4131 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.3990G>C | Q1330H 2D  AIThe SynGAP1 missense variant Q1330H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus also reports it as likely benign, and Foldetta (which integrates FoldX‑MD and Rosetta stability calculations) has no available result for this residue. Based on the preponderance of benign predictions from multiple independent algorithms and the lack of pathogenic evidence, the variant is most likely benign. This conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.557 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.91 | Neutral | 0.969 | Probably Damaging | 0.732 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.1190 | 0.3996 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3990G>T | Q1330H 2D AIThe SynGAP1 missense variant Q1330H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus also reports it as likely benign, and Foldetta (which integrates FoldX‑MD and Rosetta stability calculations) has no available result for this residue. Based on the preponderance of benign predictions from multiple independent algorithms and the lack of pathogenic evidence, the variant is most likely benign. This conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.557 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.91 | Neutral | 0.969 | Probably Damaging | 0.732 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.1190 | 0.3996 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3308G>A | R1103H 2D  AIThe SynGAP1 missense variant R1103H is listed in ClinVar (ID 577408.0) as benign and is present in gnomAD (variant ID 6‑33443860‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of predictions support a benign impact, and this conclusion aligns with the ClinVar benign classification, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Benign/Likely benign | 3 | 6-33443860-G-A | 31 | 2.03e-5 | -3.622 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.97 | Neutral | 0.996 | Probably Damaging | 0.733 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2977 | 0.2380 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.3364G>T | G1122C 2D  AIThe SynGAP1 missense variant G1122C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443916‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence—including the high‑confidence tools—supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | 6-33443916-G-T | -8.895 | Likely Pathogenic | 0.110 | Likely Benign | Likely Benign | 0.375 | Likely Benign | -1.30 | Neutral | 0.975 | Probably Damaging | 0.733 | Possibly Damaging | 4.48 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.1343 | 0.4227 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||
| c.371C>A | A124E 2D  AIThe SynGAP1 missense variant A124E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for A124E, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.444 | Likely Benign | 0.667 | Likely Pathogenic | Likely Benign | 0.208 | Likely Benign | -1.21 | Neutral | 0.993 | Probably Damaging | 0.733 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1498 | 0.2233 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1952A>T | E651V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651V missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools split in their assessment: benign‑predicted scores include REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic‑predicted scores come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX give uncertain results. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans pathogenic (3 pathogenic vs. 1 benign); Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of tools (including the high‑accuracy SGM Consensus) suggest a pathogenic impact, whereas Foldetta and several other predictors indicate benign. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -10.025 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.63 | Ambiguous | 0.1 | 0.25 | Likely Benign | 0.44 | Likely Benign | 0.21 | Likely Benign | 0.467 | Likely Benign | -5.53 | Deleterious | 0.988 | Probably Damaging | 0.734 | Possibly Damaging | 3.27 | Benign | 0.05 | Affected | 0.0824 | 0.6136 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1961A>T | E654V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654V missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and AlphaMissense‑Optimized are inconclusive. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools (8 pathogenic vs. 4 benign) and the SGM‑Consensus result support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.306 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | -0.33 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | 0.540 | Likely Pathogenic | -6.66 | Deleterious | 0.988 | Probably Damaging | 0.734 | Possibly Damaging | 3.31 | Benign | 0.01 | Affected | 0.0686 | 0.4757 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.121C>A | R41S 2D AIThe SynGAP1 missense variant R41S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R41S, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.311707 | Structured | 0.431757 | Uncertain | 0.344 | 0.765 | 0.375 | -3.367 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.130 | Likely Benign | -0.22 | Neutral | 0.686 | Possibly Damaging | 0.735 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 0.3190 | 0.5013 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.1945A>G | M649V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M649V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With 8 pathogenic versus 3 benign predictions, the overall evidence favors a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -9.907 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 2.84 | Destabilizing | 0.3 | 2.55 | Destabilizing | 2.70 | Destabilizing | 1.05 | Destabilizing | 0.370 | Likely Benign | -3.99 | Deleterious | 0.997 | Probably Damaging | 0.735 | Possibly Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.2389 | 0.3121 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.3725A>C | E1242A 2D AIThe SynGAP1 missense variant E1242A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (five pathogenic vs. three benign) predict a pathogenic impact. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.557691 | Disordered | 0.456349 | Uncertain | 0.870 | 0.549 | 0.500 | -5.654 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.187 | Likely Benign | -4.66 | Deleterious | 0.939 | Possibly Damaging | 0.735 | Possibly Damaging | 2.21 | Pathogenic | 0.00 | Affected | 0.2738 | 0.4169 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2765G>A | R922Q 2D AIThe SynGAP1 missense variant R922Q is listed in ClinVar as Benign (ClinVar ID 2917638.0) and is present in gnomAD (ID 6‑33443317‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same set of high‑confidence predictors) also as benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | Benign | 1 | 6-33443317-G-A | 7 | 4.34e-6 | -3.295 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.27 | Neutral | 0.992 | Probably Damaging | 0.736 | Possibly Damaging | 2.57 | Benign | 0.20 | Tolerated | 3.77 | 5 | 0.3444 | 0.2602 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2302G>C | D768H 2D AIThe SynGAP1 D768H missense variant is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of predictions (5 benign vs. 4 pathogenic) and the high‑accuracy benign call suggest the variant is most likely benign, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -8.673 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | -1.85 | Neutral | 0.966 | Probably Damaging | 0.737 | Possibly Damaging | 4.03 | Benign | 0.12 | Tolerated | 0.1450 | 0.8136 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.647A>C | Q216P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216P is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus indicates likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. premPS is inconclusive and is treated as unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -13.128 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 4.35 | Destabilizing | 0.8 | 4.05 | Destabilizing | 4.20 | Destabilizing | 0.53 | Ambiguous | 0.830 | Likely Pathogenic | -4.69 | Deleterious | 0.989 | Probably Damaging | 0.737 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0.2603 | 0.5736 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.2002T>G | S668A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S668A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—AlphaMissense‑Default and FoldX—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Taking all evidence together, the majority of predictions (seven benign versus four pathogenic) and the two high‑accuracy benign calls suggest that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -12.011 | Likely Pathogenic | 0.506 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.3 | -0.44 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.399 | Likely Benign | -2.99 | Deleterious | 0.887 | Possibly Damaging | 0.738 | Possibly Damaging | 3.28 | Benign | 0.19 | Tolerated | 0.4866 | 0.3967 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||
| c.2068T>G | S690A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta reports an uncertain stability change, so these results are treated as unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -8.763 | Likely Pathogenic | 0.318 | Likely Benign | Likely Benign | -0.82 | Ambiguous | 0.0 | -2.17 | Stabilizing | -1.50 | Ambiguous | 0.45 | Likely Benign | 0.217 | Likely Benign | -2.55 | Deleterious | 0.887 | Possibly Damaging | 0.738 | Possibly Damaging | 3.45 | Benign | 0.21 | Tolerated | 0.4619 | 0.3131 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||
| c.2395C>A | P799T 2D AIThe SynGAP1 missense variant P799T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P799T, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.470 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -0.82 | Neutral | 0.951 | Possibly Damaging | 0.738 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 0.1522 | 0.5257 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.3641G>A | R1214Q 2D AIThe SynGAP1 missense variant R1214Q is catalogued in gnomAD (6‑33446633‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect for R1214Q, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | 6-33446633-G-A | 6 | 3.72e-6 | -6.059 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.69 | Neutral | 0.993 | Probably Damaging | 0.738 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 3.77 | 5 | 0.2162 | 0.1530 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||
| c.2039A>G | E680G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E680G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a pathogenic effect, with high‑accuracy methods split but tipping toward pathogenicity. The variant’s status in ClinVar is unknown, so there is no contradiction between the predictions and existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -11.396 | Likely Pathogenic | 0.743 | Likely Pathogenic | Likely Benign | 0.67 | Ambiguous | 0.2 | 0.11 | Likely Benign | 0.39 | Likely Benign | 0.44 | Likely Benign | 0.411 | Likely Benign | -5.48 | Deleterious | 0.998 | Probably Damaging | 0.739 | Possibly Damaging | 3.47 | Benign | 0.01 | Affected | 0.2708 | 0.6228 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.892C>A | P298T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for P298T, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.366 | In-Between | 0.104 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.24 | Ambiguous | 0.04 | Likely Benign | 0.209 | Likely Benign | -0.13 | Neutral | 0.939 | Possibly Damaging | 0.739 | Possibly Damaging | 1.96 | Pathogenic | 1.00 | Tolerated | 0.1595 | 0.6349 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.2408A>C | K803T 2D AIThe SynGAP1 missense variant K803T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicate it is likely pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM‑Consensus indicates it is likely pathogenic; a Foldetta stability analysis is not available. Overall, the balance of evidence points to a pathogenic effect for K803T, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -3.571 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.121 | Likely Benign | -2.90 | Deleterious | 0.946 | Possibly Damaging | 0.741 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.2417 | 0.4395 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.1168G>T | G390W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, premPS, and PROVEAN, whereas the remaining tools—REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict, and Foldetta also indicates pathogenic. With the majority of evidence pointing to a deleterious effect, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.405 | Likely Pathogenic | 0.487 | Ambiguous | Likely Benign | 3.69 | Destabilizing | 1.9 | 5.31 | Destabilizing | 4.50 | Destabilizing | 0.14 | Likely Benign | 0.639 | Likely Pathogenic | -1.11 | Neutral | 0.987 | Probably Damaging | 0.744 | Possibly Damaging | 1.31 | Pathogenic | 0.00 | Affected | 0.0917 | 0.4368 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.2203A>G | S735G 2D  AIThe SynGAP1 missense variant S735G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the majority of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -5.986 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.55 | Neutral | 0.953 | Possibly Damaging | 0.744 | Possibly Damaging | 2.68 | Benign | 0.23 | Tolerated | 0.2777 | 0.4089 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2671C>T | L891F 2D  AIThe SynGAP1 missense variant L891F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available. Overall, the majority of evidence points to a benign effect for L891F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.505861 | Binding | 0.305 | 0.923 | 0.750 | -5.650 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.80 | Neutral | 0.970 | Probably Damaging | 0.744 | Possibly Damaging | 2.66 | Benign | 0.04 | Affected | 0.0652 | 0.2907 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.166C>G | L56V 2D AIThe SynGAP1 missense variant L56V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign (2 benign vs 1 pathogenic, 1 uncertain). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the L56V variant, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.342579 | Structured | 0.476218 | Uncertain | 0.495 | 0.657 | 0.000 | -8.104 | Likely Pathogenic | 0.471 | Ambiguous | Likely Benign | 0.123 | Likely Benign | -0.99 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1635 | 0.3655 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.169C>A | L57I 2D  AIThe SynGAP1 missense variant L57I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for the L57I variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -3.681 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.07 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0973 | 0.4106 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.169C>G | L57V 2D AIThe SynGAP1 missense variant L57V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -3.598 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.14 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.1533 | 0.4006 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.175C>G | L59V 2D AIThe SynGAP1 missense variant L59V is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -4.465 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.049 | Likely Benign | -1.15 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 3.36 | Benign | 0.00 | Affected | 0.1508 | 0.3217 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3407A>C | Q1136P 2D AIThe SynGAP1 missense variant Q1136P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.067 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.364 | Likely Benign | -1.06 | Neutral | 0.961 | Probably Damaging | 0.745 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2188 | 0.5344 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2050G>A | D684N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684N is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also reports it as likely pathogenic, and the Foldetta stability analysis is inconclusive. Protein‑stability predictors FoldX and Rosetta likewise return uncertain results. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | Uncertain | 1 | -13.155 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.47 | Ambiguous | 0.8 | 1.76 | Ambiguous | 1.62 | Ambiguous | 0.37 | Likely Benign | 0.382 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.746 | Possibly Damaging | 3.39 | Benign | 0.01 | Affected | 0.1157 | 0.6373 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||
| c.604G>C | E202Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -7.129 | In-Between | 0.456 | Ambiguous | Likely Benign | -0.16 | Likely Benign | 0.0 | 0.23 | Likely Benign | 0.04 | Likely Benign | -0.13 | Likely Benign | 0.175 | Likely Benign | -1.39 | Neutral | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 4.07 | Benign | 0.02 | Affected | 0.0949 | 0.6792 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.620A>C | K207T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K207T, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -11.002 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.15 | Destabilizing | 0.8 | 0.57 | Ambiguous | 1.36 | Ambiguous | 0.78 | Ambiguous | 0.239 | Likely Benign | -4.57 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.99 | Benign | 0.07 | Tolerated | 0.1636 | 0.4031 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.632G>A | S211N 2D  AIThe SynGAP1 S211N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and premPS. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall prediction leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.995 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 1.2 | 1.39 | Ambiguous | 1.00 | Ambiguous | 1.21 | Destabilizing | 0.174 | Likely Benign | -2.22 | Neutral | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.95 | Benign | 0.09 | Tolerated | 0.1534 | 0.4863 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.706G>A | A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -8.319 | Likely Pathogenic | 0.240 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.16 | Ambiguous | 0.83 | Ambiguous | 0.811 | Likely Pathogenic | -3.35 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 0.1342 | 0.6926 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.722A>C | K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.911 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 0.4 | 0.06 | Likely Benign | 1.03 | Ambiguous | 0.60 | Ambiguous | 0.853 | Likely Pathogenic | -5.14 | Deleterious | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 5.74 | Benign | 0.03 | Affected | 0.2021 | 0.3951 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.2674T>A | S892T 2D AIThe SynGAP1 missense variant S892T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.806 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.09 | Neutral | 0.975 | Probably Damaging | 0.748 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 0.1606 | 0.5857 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2692T>G | S898A 2D AIThe SynGAP1 missense variant S898A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign classification. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence from both general and high‑accuracy predictors suggests that S898A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -3.932 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.98 | Neutral | 0.942 | Possibly Damaging | 0.748 | Possibly Damaging | 2.63 | Benign | 0.03 | Affected | 0.4552 | 0.5516 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2654C>A | P885H 2D  AIThe SynGAP1 missense variant P885H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -5.239 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.68 | Neutral | 0.938 | Possibly Damaging | 0.749 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 0.1552 | 0.5280 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.607G>A | D203N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D203N is reported in gnomAD (variant ID 6-33435249‑G‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar; ESM1b is uncertain. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the aggregate evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | 6-33435249-G-A | 1 | 6.20e-7 | -7.465 | In-Between | 0.159 | Likely Benign | Likely Benign | -0.19 | Likely Benign | 0.1 | -0.12 | Likely Benign | -0.16 | Likely Benign | -0.03 | Likely Benign | 0.121 | Likely Benign | -2.26 | Neutral | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 4.06 | Benign | 0.06 | Tolerated | 3.44 | 10 | 0.0800 | 0.4296 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.752A>C | K251T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic prediction, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic effect for K251T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -10.552 | Likely Pathogenic | 0.841 | Likely Pathogenic | Ambiguous | 1.21 | Ambiguous | 0.4 | 0.50 | Ambiguous | 0.86 | Ambiguous | 0.46 | Likely Benign | 0.742 | Likely Pathogenic | -2.72 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.76 | Benign | 0.28 | Tolerated | 0.2353 | 0.2852 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.761A>C | K254T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to SIFT and FATHMM. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic effect for K254T, and this conclusion does not conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -13.793 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.51 | Ambiguous | 0.0 | 1.92 | Ambiguous | 1.22 | Ambiguous | 0.62 | Ambiguous | 0.883 | Likely Pathogenic | -5.14 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.88 | Benign | 0.06 | Tolerated | 0.1825 | 0.2562 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1226T>A | M409K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409K has no ClinVar record and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, SIFT, and FATHMM, while pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -13.618 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.3 | 0.29 | Likely Benign | 0.61 | Ambiguous | 1.45 | Destabilizing | 0.490 | Likely Benign | -4.26 | Deleterious | 0.769 | Possibly Damaging | 0.750 | Possibly Damaging | 4.18 | Benign | 0.40 | Tolerated | 0.1318 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.127G>T | G43C 2D AIThe SynGAP1 missense variant G43C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.308712 | Structured | 0.431462 | Uncertain | 0.396 | 0.762 | 0.375 | -4.599 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.90 | Neutral | 0.987 | Probably Damaging | 0.750 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.1445 | 0.3438 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2848G>T | G950C 2D AIThe SynGAP1 missense variant G950C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (five pathogenic vs. four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -9.589 | Likely Pathogenic | 0.092 | Likely Benign | Likely Benign | 0.395 | Likely Benign | -0.35 | Neutral | 0.983 | Probably Damaging | 0.750 | Possibly Damaging | 2.26 | Pathogenic | 0.01 | Affected | 0.1406 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3098C>G | S1033C 2D AIThe SynGAP1 missense variant S1033C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1033C, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -6.263 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.39 | Neutral | 0.992 | Probably Damaging | 0.750 | Possibly Damaging | 2.68 | Benign | 0.12 | Tolerated | 0.1031 | 0.5704 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3101C>A | P1034H 2D AIThe SynGAP1 missense variant P1034H is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.634 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.083 | Likely Benign | -3.17 | Deleterious | 0.938 | Possibly Damaging | 0.750 | Possibly Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0.1776 | 0.5451 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3146C>A | P1049H 2D AIThe SynGAP1 missense variant P1049H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.427 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -2.06 | Neutral | 0.978 | Probably Damaging | 0.750 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 0.1800 | 0.5070 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3151G>T | G1051C 2D AIThe SynGAP1 missense variant G1051C is listed in ClinVar as Pathogenic and is not reported in gnomAD. Functional prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. High‑accuracy methods give a benign result from AlphaMissense‑Optimized; the SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is tied (2 benign vs. 2 pathogenic) and therefore inconclusive, and Foldetta’s stability prediction is unavailable. Overall, the majority of predictions lean toward a benign effect, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Likely Pathogenic | 1 | -9.050 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.497 | Likely Benign | -0.90 | Neutral | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | -0.74 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.1322 | 0.4612 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||
| c.3392C>A | P1131H 2D AIThe SynGAP1 missense variant P1131H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -5.207 | Likely Benign | 0.454 | Ambiguous | Likely Benign | 0.357 | Likely Benign | -3.50 | Deleterious | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | 5.24 | Benign | 0.00 | Affected | 0.1519 | 0.5546 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.365C>A | P122H 2D AIThe SynGAP1 missense variant P122H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for P122H. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -4.993 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -1.82 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2306 | 0.4213 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.374C>A | P125H 2D AIThe SynGAP1 missense variant P125H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of conventional predictors (five pathogenic vs four benign) lean toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the inconclusive SGM Consensus temper this view. No ClinVar annotation is present, so there is no reported status to contradict the computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -5.177 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.235 | Likely Benign | -4.18 | Deleterious | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 2.82 | Benign | 0.01 | Affected | 0.1598 | 0.4263 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.383C>A | P128H 2D AIThe SynGAP1 missense variant P128H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -4.806 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.169 | Likely Benign | -1.90 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2207 | 0.3414 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3896T>A | L1299H 2D AIThe SynGAP1 missense variant L1299H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -4.586 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.317 | Likely Benign | -3.83 | Deleterious | 0.992 | Probably Damaging | 0.750 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1293 | 0.1273 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.533A>T | K178M 2D  AIThe SynGAP1 missense variant K178M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -13.585 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -3.95 | Deleterious | 0.992 | Probably Damaging | 0.751 | Possibly Damaging | 3.83 | Benign | 0.00 | Affected | 0.1486 | 0.3607 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3448G>T | A1150S 2D AIThe SynGAP1 missense variant A1150S is reported in gnomAD (ID 6‑33444483‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | 6-33444483-G-T | 7 | 4.34e-6 | -2.656 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.49 | Neutral | 0.951 | Possibly Damaging | 0.752 | Possibly Damaging | 2.37 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.2656 | 0.5694 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.3667C>A | L1223M 2D AIThe SynGAP1 missense variant L1223M is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also classifies the variant as benign, and Foldetta results are unavailable. Taken together, the balance of evidence favors a benign effect for L1223M, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.608892 | Disordered | 0.436267 | Uncertain | 0.868 | 0.540 | 0.375 | -5.759 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.166 | Likely Benign | -1.29 | Neutral | 0.981 | Probably Damaging | 0.752 | Possibly Damaging | 1.50 | Pathogenic | 0.04 | Affected | 0.0667 | 0.3014 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2714G>T | R905L 2D AIThe SynGAP1 missense variant R905L is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (allele ID 6‑33443266‑G‑T). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of predictions leans toward a benign interpretation, and this conclusion does not contradict the ClinVar status, which currently has no assertion for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.618085 | Binding | 0.291 | 0.920 | 0.250 | 6-33443266-G-T | -3.284 | Likely Benign | 0.709 | Likely Pathogenic | Likely Benign | 0.242 | Likely Benign | -2.55 | Deleterious | 0.963 | Probably Damaging | 0.753 | Possibly Damaging | 2.61 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1676 | 0.4905 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||
| c.2846G>A | G949D 2D AIThe SynGAP1 missense variant G949D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (5 pathogenic vs. 4 benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -8.692 | Likely Pathogenic | 0.239 | Likely Benign | Likely Benign | 0.316 | Likely Benign | 0.25 | Neutral | 0.945 | Possibly Damaging | 0.753 | Possibly Damaging | 2.21 | Pathogenic | 0.02 | Affected | 0.1927 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.611C>G | S204C 2D 3DClick to see structure in 3D Viewer AISynGAP1 S204C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. FoldX and Rosetta individually report uncertain stability changes. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | Uncertain | 1 | -6.613 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.4 | -1.13 | Ambiguous | -0.24 | Likely Benign | 0.10 | Likely Benign | 0.148 | Likely Benign | -0.64 | Neutral | 0.978 | Probably Damaging | 0.753 | Possibly Damaging | 4.13 | Benign | 0.05 | Affected | 3.44 | 10 | 0.0665 | 0.5237 | 0 | -1 | 3.3 | 16.06 | 223.6 | -13.8 | 0.6 | 0.3 | 0.0 | 0.2 | X | Uncertain | The hydroxyl-containing Ser204, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by the thiol-containing cysteine. In the WT simulations, Ser204 simultaneously forms hydrogen bonds with the backbone carbonyl of Asp201 and the hydroxyl group of Thr224, helping to stabilize the two anti-parallel β strands (res. Ile205-Lys207 and Cys219-Thr223) at the end of the β sheet. Since the thiol group of cysteine forms weaker hydrogen bonds than the hydroxyl group of serine, Cys204 does not maintain the hydrogen bond network as stably as Ser204 in the variant simulations. However, because the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||||
| c.659T>G | F220C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220C is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.0 | 5.03 | Destabilizing | 4.35 | Destabilizing | 2.22 | Destabilizing | 0.941 | Likely Pathogenic | -6.72 | Deleterious | 0.994 | Probably Damaging | 0.753 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | 0.2264 | 0.2012 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.955G>T | A319S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -7.109 | In-Between | 0.093 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.09 | Likely Benign | 0.13 | Likely Benign | 0.165 | Likely Benign | -0.58 | Neutral | 0.978 | Probably Damaging | 0.754 | Possibly Damaging | 2.02 | Pathogenic | 0.12 | Tolerated | 0.2537 | 0.4703 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1967A>C | E656A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further reveal that AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing or inconclusive. Based on the overall evidence, the variant is most likely pathogenic; this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -14.373 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.12 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.11 | Likely Benign | -0.13 | Likely Benign | 0.499 | Likely Benign | -5.38 | Deleterious | 0.985 | Probably Damaging | 0.755 | Possibly Damaging | 3.46 | Benign | 0.03 | Affected | 0.4244 | 0.6271 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2009T>G | L670R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign effect. There is no ClinVar annotation to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -9.801 | Likely Pathogenic | 0.552 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.1 | 1.42 | Ambiguous | 1.03 | Ambiguous | 0.67 | Ambiguous | 0.193 | Likely Benign | -1.74 | Neutral | 0.993 | Probably Damaging | 0.755 | Possibly Damaging | 3.43 | Benign | 0.41 | Tolerated | 0.1327 | 0.1145 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.2959G>A | D987N 2D AIThe SynGAP1 D987N missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -5.035 | Likely Benign | 0.698 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.42 | Neutral | 0.943 | Possibly Damaging | 0.755 | Possibly Damaging | 2.41 | Pathogenic | 0.49 | Tolerated | 0.1331 | 0.7427 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.1915T>G | F639V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; Rosetta is uncertain and is therefore not counted. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.910 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 4.17 | Destabilizing | 0.1 | 1.18 | Ambiguous | 2.68 | Destabilizing | 1.47 | Destabilizing | 0.560 | Likely Pathogenic | -6.97 | Deleterious | 0.992 | Probably Damaging | 0.756 | Possibly Damaging | 3.08 | Benign | 0.02 | Affected | 0.2074 | 0.1583 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.3982C>T | R1328W 2D AIThe SynGAP1 missense variant R1328W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451856‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic outcome. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta results are unavailable. Taken together, the majority of high‑confidence predictions favor a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | 6-33451856-C-T | 4 | 2.56e-6 | -7.022 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.756 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1349 | 0.2906 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.4002C>A | N1334K 2D AIThe SynGAP1 missense variant N1334K is listed in gnomAD (ID 6‑33451876‑C‑A) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy methods do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | 6-33451876-C-A | -4.875 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | -3.49 | Deleterious | 0.979 | Probably Damaging | 0.756 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2355 | 0.5163 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.4002C>G | N1334K 2D AIThe SynGAP1 missense variant N1334K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 tie and therefore unavailable; Foldetta predictions are not provided. Overall, the balance of evidence favors a pathogenic effect for N1334K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -4.875 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -3.49 | Deleterious | 0.979 | Probably Damaging | 0.756 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2355 | 0.5163 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3800T>G | M1267R 2D AIThe SynGAP1 missense variant M1267R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Grouping by consensus, two tools predict benign and six predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -4.990 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.366 | Likely Benign | -5.03 | Deleterious | 0.982 | Probably Damaging | 0.757 | Possibly Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.1555 | 0.0837 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3956C>T | A1319V 2D AIThe SynGAP1 missense variant A1319V is reported in gnomAD (ID 6‑33451830‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319V, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-T | 1 | 7.16e-7 | -5.015 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.17 | Neutral | 0.971 | Probably Damaging | 0.757 | Possibly Damaging | 4.14 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1583 | 0.6127 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2051A>C | D684A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only premPS and FATHMM predict a benign outcome. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No evidence is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.1 | 2.85 | Destabilizing | 3.10 | Destabilizing | 0.28 | Likely Benign | 0.547 | Likely Pathogenic | -7.98 | Deleterious | 0.994 | Probably Damaging | 0.758 | Possibly Damaging | 3.42 | Benign | 0.01 | Affected | 0.3477 | 0.5423 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.2107C>A | L703I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and Rosetta. Predictions that are uncertain or inconclusive (FoldX, Foldetta, premPS, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of high‑confidence tools predict a benign impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -9.332 | Likely Pathogenic | 0.345 | Ambiguous | Likely Benign | 1.44 | Ambiguous | 0.1 | 2.21 | Destabilizing | 1.83 | Ambiguous | 0.61 | Ambiguous | 0.108 | Likely Benign | -1.50 | Neutral | 0.982 | Probably Damaging | 0.758 | Possibly Damaging | 3.38 | Benign | 0.00 | Affected | 0.0909 | 0.3079 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2111G>T | S704I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704I lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) report a pathogenic or likely pathogenic outcome. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods specifically give AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -14.222 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 1.63 | Ambiguous | 0.1 | 1.32 | Ambiguous | 1.48 | Ambiguous | 0.29 | Likely Benign | 0.232 | Likely Benign | -4.05 | Deleterious | 0.997 | Probably Damaging | 0.758 | Possibly Damaging | 3.49 | Benign | 0.02 | Affected | 0.0727 | 0.4798 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.656G>A | C219Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | Uncertain | 1 | -14.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.98 | Destabilizing | 2.0 | 2.84 | Destabilizing | 5.91 | Destabilizing | 0.55 | Ambiguous | 0.812 | Likely Pathogenic | -9.09 | Deleterious | 0.990 | Probably Damaging | 0.758 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.0772 | 0.3285 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||
| c.1027G>T | V343F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and premPS, whereas pathogenic predictions are made by SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of predictions support a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -10.709 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 1.51 | Ambiguous | 0.4 | 1.28 | Ambiguous | 1.40 | Ambiguous | 0.23 | Likely Benign | 0.324 | Likely Benign | -3.37 | Deleterious | 0.976 | Probably Damaging | 0.759 | Possibly Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.0915 | 0.4552 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.3422C>T | P1141L 2D AIThe SynGAP1 missense variant P1141L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic versus one benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that P1141L is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -3.817 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -4.64 | Deleterious | 0.954 | Possibly Damaging | 0.759 | Possibly Damaging | 0.98 | Pathogenic | 0.00 | Affected | 0.2147 | 0.6099 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.62T>G | F21C 2D AIThe SynGAP1 missense variant F21C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F21C. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | -3.698 | Likely Benign | 0.686 | Likely Pathogenic | Likely Benign | 0.151 | Likely Benign | -0.31 | Neutral | 0.880 | Possibly Damaging | 0.759 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 0.2873 | 0.2171 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.2603A>C | D868A 2D AIThe SynGAP1 D868A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the balance of evidence—including the benign prediction from the most accurate AlphaMissense‑Optimized model and the majority of benign calls—suggests that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -2.764 | Likely Benign | 0.702 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -2.75 | Deleterious | 0.972 | Probably Damaging | 0.760 | Possibly Damaging | 2.54 | Benign | 0.21 | Tolerated | 0.4590 | 0.6990 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3436C>G | P1146A 2D  AIThe SynGAP1 missense variant P1146A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P1146A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.896 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.300 | Likely Benign | -3.56 | Deleterious | 0.972 | Probably Damaging | 0.760 | Possibly Damaging | 5.53 | Benign | 0.00 | Affected | 0.3516 | 0.4791 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>T | P1146S 2D  AIThe SynGAP1 missense variant P1146S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33444471-C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | 6-33444471-C-T | 2 | 1.24e-6 | -3.045 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.470 | Likely Benign | -3.66 | Deleterious | 0.945 | Possibly Damaging | 0.760 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3408 | 0.5186 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.577G>T | A193S 2D AIThe SynGAP1 missense variant A193S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -2.408 | Likely Benign | 0.533 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -1.62 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.04 | Benign | 0.04 | Affected | 0.2595 | 0.5852 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.578C>G | A193G 2D AIThe SynGAP1 missense variant A193G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (5) than benignity (3), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.822 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -2.61 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 0.2283 | 0.4999 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.583G>T | A195S 2D AIThe SynGAP1 missense variant A195S is listed in gnomAD (6‑33435225‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy predictors) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | 6-33435225-G-T | 1 | 6.20e-7 | -4.936 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -1.13 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.10 | Benign | 0.08 | Tolerated | 3.54 | 6 | 0.1846 | 0.4427 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.584C>G | A195G 2D AIThe SynGAP1 missense variant A195G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that AlphaMissense‑Optimized remains uncertain, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—favors a pathogenic outcome. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact for A195G, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -7.186 | In-Between | 0.907 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -2.64 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.01 | Benign | 0.05 | Affected | 0.1694 | 0.3388 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.592C>A | L198I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198I is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -10.411 | Likely Pathogenic | 0.563 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.65 | Ambiguous | 0.10 | Likely Benign | 0.234 | Likely Benign | -1.72 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 3.43 | Benign | 0.00 | Affected | 0.0921 | 0.3307 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||
| c.598T>G | L200V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the Foldetta stability assessment. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign effect; there is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -6.917 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 2.15 | Destabilizing | 0.2 | 1.85 | Ambiguous | 2.00 | Destabilizing | 0.92 | Ambiguous | 0.098 | Likely Benign | -1.07 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.09 | Benign | 0.24 | Tolerated | 0.1593 | 0.3607 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.730G>A | E244K 2D AISynGAP1 missense variant E244K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from FoldX, Rosetta, Foldetta, SIFT, and FATHMM, whereas pathogenic predictions are reported by REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. With the majority of consensus tools leaning toward pathogenic and the two high‑accuracy pathogenic predictions outweighing the benign Foldetta result, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -13.975 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 1.0 | 0.45 | Likely Benign | 0.43 | Likely Benign | 0.80 | Ambiguous | 0.841 | Likely Pathogenic | -3.37 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.82 | Benign | 0.07 | Tolerated | 0.1887 | 0.6177 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.746C>G | A249G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for A249G, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -9.678 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 1.04 | Ambiguous | 0.2 | 2.02 | Destabilizing | 1.53 | Ambiguous | 1.19 | Destabilizing | 0.607 | Likely Pathogenic | -2.97 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.59 | Benign | 0.04 | Affected | 0.1667 | 0.2675 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.746C>T | A249V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A249V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, no high‑accuracy tool provides a definitive pathogenic or benign verdict. Overall, the majority of available predictions (seven pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -9.417 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 1.48 | Ambiguous | 0.6 | 0.51 | Ambiguous | 1.00 | Ambiguous | 0.41 | Likely Benign | 0.652 | Likely Pathogenic | -2.47 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.76 | Benign | 0.03 | Affected | 0.0737 | 0.4677 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.145T>C | C49R 2D AIThe SynGAP1 missense variant C49R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and no Foldetta (FoldX‑MD/Rosetta) result is available. Taken together, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -10.000 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.320 | Likely Benign | -3.53 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 0.1605 | 0.2120 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||||||||||||
| c.146G>A | C49Y 2D AIThe SynGAP1 missense variant C49Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for C49Y. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -11.097 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | -3.38 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.1016 | 0.3172 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||||||||||||
| c.1613A>C | E538A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (7 pathogenic vs 6 benign) lean toward a pathogenic interpretation, and this does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -9.888 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.0 | -0.06 | Likely Benign | 0.14 | Likely Benign | 0.16 | Likely Benign | 0.269 | Likely Benign | -4.66 | Deleterious | 0.944 | Possibly Damaging | 0.761 | Possibly Damaging | 3.36 | Benign | 0.05 | Affected | 0.3995 | 0.4187 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2581T>C | S861P 2D AIThe SynGAP1 missense variant S861P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for S861P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.540903 | Binding | 0.285 | 0.797 | 0.250 | -4.256 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.65 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 3.93 | Benign | 0.13 | Tolerated | 0.1830 | 0.6011 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>G | L1028R 2D AIThe SynGAP1 missense variant L1028R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.204 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.167 | Likely Benign | -0.24 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 2.75 | Benign | 0.84 | Tolerated | 0.1328 | 0.1603 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3302C>G | P1101R 2D AIThe SynGAP1 missense variant P1101R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.772 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.28 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 4.27 | Benign | 0.36 | Tolerated | 0.1497 | 0.4644 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3311C>G | P1104R 2D AIThe SynGAP1 missense variant P1104R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.864 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.64 | Neutral | 0.986 | Probably Damaging | 0.761 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 0.1387 | 0.3703 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3424T>C | S1142P 2D AIThe SynGAP1 missense variant S1142P is listed in ClinVar (ID 2747352.0) as Benign and is present in gnomAD (variant ID 6‑33444459‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | Likely Benign | 1 | 6-33444459-T-C | 1 | 6.20e-7 | -2.713 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.19 | Neutral | 0.918 | Possibly Damaging | 0.761 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2080 | 0.5618 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.3917A>T | N1306I 2D AIThe SynGAP1 missense variant N1306I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.234 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -6.15 | Deleterious | 0.890 | Possibly Damaging | 0.761 | Possibly Damaging | 2.56 | Benign | 0.00 | Affected | 0.0837 | 0.6672 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.959T>C | V320A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V320A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy consensus leans toward pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -5.488 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 1.26 | Ambiguous | 0.7 | 1.48 | Ambiguous | 1.37 | Ambiguous | 1.27 | Destabilizing | 0.179 | Likely Benign | -3.05 | Deleterious | 0.948 | Possibly Damaging | 0.761 | Possibly Damaging | 1.84 | Pathogenic | 0.35 | Tolerated | 0.2405 | 0.1903 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.1523A>C | D508A 2D 3DClick to see structure in 3D Viewer AISynGAP1 D508A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give a split result: AlphaMissense‑Optimized predicts benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. No prediction or stability result is missing; all available outputs are considered. Overall, the predictions are evenly divided between benign and pathogenic, with no clear consensus. Therefore, the variant is inconclusive; it is not contradictory to the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -11.434 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | -0.18 | Likely Benign | 0.2 | 1.84 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | 0.339 | Likely Benign | -7.37 | Deleterious | 0.988 | Probably Damaging | 0.762 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.3758 | 0.4241 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.3586A>G | K1196E 2D  AIThe SynGAP1 missense variant K1196E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools are divided: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -6.382 | Likely Benign | 0.734 | Likely Pathogenic | Likely Benign | 0.358 | Likely Benign | -0.02 | Neutral | 0.961 | Probably Damaging | 0.764 | Possibly Damaging | 5.38 | Benign | 0.42 | Tolerated | 0.3272 | 0.0720 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.2353C>A | R785S 2D AIThe SynGAP1 missense variant R785S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -2.926 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.93 | Deleterious | 0.980 | Probably Damaging | 0.765 | Possibly Damaging | 2.34 | Pathogenic | 0.01 | Affected | 0.3523 | 0.3800 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2560C>A | R854S 2D AIThe SynGAP1 missense variant R854S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the preponderance of evidence points to a benign impact for R854S, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -1.42 | Neutral | 0.960 | Probably Damaging | 0.765 | Possibly Damaging | 4.14 | Benign | 0.26 | Tolerated | 0.3183 | 0.4687 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2561G>T | R854L 2D AIThe SynGAP1 missense variant R854L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R854L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.573 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -1.78 | Neutral | 0.960 | Probably Damaging | 0.765 | Possibly Damaging | 4.11 | Benign | 0.03 | Affected | 0.1875 | 0.5223 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>A | P1307Q 2D AIThe SynGAP1 missense variant P1307Q is listed in ClinVar (ID 982827.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451794‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | Uncertain | 1 | 6-33451794-C-A | -4.227 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.88 | Neutral | 0.988 | Probably Damaging | 0.765 | Possibly Damaging | 2.82 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1629 | 0.4464 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||
| c.200T>A | L67Q 2D AIThe SynGAP1 missense variant L67Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.948 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -0.66 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0861 | 0.0719 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.200T>C | L67P 2D AIThe SynGAP1 missense variant L67P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -2.852 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -0.80 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.3052 | 0.1382 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.200T>G | L67R 2D AIThe SynGAP1 missense variant L67R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Thus, the variant is most likely benign based on current predictive tools. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.430 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.115 | Likely Benign | -0.84 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.1159 | 0.0719 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.203T>A | L68Q 2D AIThe SynGAP1 missense variant L68Q is listed in gnomAD (6‑33425811‑T‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome, reflecting the majority of benign calls. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are not available. Based on the available evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.470567 | Uncertain | 0.405 | 0.768 | 0.250 | 6-33425811-T-A | 5 | 3.10e-6 | -3.436 | Likely Benign | 0.826 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -0.14 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0864 | 0.0919 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||
| c.203T>C | L68P 2D AIThe SynGAP1 missense variant L68P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward pathogenic, but the consensus from SGM and the high‑accuracy AlphaMissense‑Optimized are contradictory, leaving the variant’s clinical significance uncertain. No conflict exists with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.470567 | Uncertain | 0.405 | 0.768 | 0.250 | -2.122 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.143 | Likely Benign | -0.57 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.2827 | 0.1382 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.203T>G | L68R 2D AIThe SynGAP1 missense variant L68R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign impact. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic effect. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.470567 | Uncertain | 0.405 | 0.768 | 0.250 | -3.427 | Likely Benign | 0.865 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | -0.61 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.1178 | 0.0519 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2425A>T | S809C 2D AIThe SynGAP1 missense variant S809C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -8.186 | Likely Pathogenic | 0.221 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -1.99 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1088 | 0.6174 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.248G>T | R83I 2D AIThe SynGAP1 missense variant R83I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence (seven pathogenic vs. three benign predictions) indicates that R83I is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | -4.021 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.183 | Likely Benign | -3.15 | Deleterious | 0.972 | Probably Damaging | 0.766 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.1450 | 0.3219 | -2 | -3 | 9.0 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2750C>A | P917H 2D AIThe SynGAP1 missense variant P917H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | -5.395 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -2.00 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.1584 | 0.4410 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3537G>C | K1179N 2D AIThe SynGAP1 missense variant K1179N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Among general in‑silico predictors, benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of high‑confidence predictions lean toward pathogenicity, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.637480 | Disordered | 0.558455 | Binding | 0.575 | 0.678 | 0.250 | -4.764 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.113 | Likely Benign | -1.57 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.68 | Benign | 0.00 | Affected | 0.3490 | 0.0901 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3537G>T | K1179N 2D AIThe SynGAP1 K1179N missense variant is not reported in ClinVar and has no entries in gnomAD. General in silico predictors cluster into two groups: benign predictions from REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy tools provide a mixed signal: AlphaMissense‑Optimized classifies the change as pathogenic, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta results are unavailable. Overall, the evidence is split, with no single consensus. Thus, the variant is currently inconclusive—neither clearly benign nor pathogenic—and does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.637480 | Disordered | 0.558455 | Binding | 0.575 | 0.678 | 0.250 | -4.764 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.113 | Likely Benign | -1.57 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.68 | Benign | 0.00 | Affected | 0.3490 | 0.0901 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.2414T>C | L805P 2D AIThe SynGAP1 missense variant L805P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no Foldetta data are available. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | Uncertain | 1 | -4.661 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.272 | Likely Benign | -3.40 | Deleterious | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3128 | 0.1650 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.2623G>T | A875S 2D AIThe SynGAP1 missense variant A875S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A875S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -2.719 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.07 | Neutral | 0.945 | Possibly Damaging | 0.767 | Possibly Damaging | 2.78 | Benign | 0.08 | Tolerated | 0.2607 | 0.6338 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2747T>A | V916D 2D AIThe SynGAP1 missense variant V916D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.653 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -1.48 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 2.69 | Benign | 0.01 | Affected | 0.1580 | 0.1113 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3608A>C | H1203P 2D AIThe SynGAP1 missense variant H1203P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. four benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -11.286 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.485 | Likely Benign | -2.10 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.47 | Benign | 0.26 | Tolerated | 0.1742 | 0.2820 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3674C>A | S1225Y 2D AIThe SynGAP1 missense variant S1225Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -8.360 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.419 | Likely Benign | -2.27 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.34 | Benign | 0.04 | Affected | 0.0547 | 0.4691 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3926T>G | V1309G 2D  AIThe SynGAP1 missense variant V1309G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.618 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.326 | Likely Benign | -3.40 | Deleterious | 0.391 | Benign | 0.767 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.1901 | 0.2144 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.562A>C | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S188R variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.269 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.564T>A | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method, did not provide a result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S188R variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.564T>G | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method, did not provide a result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.263 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.632G>T | S211I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S211I missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -17.090 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 1.1 | 1.05 | Ambiguous | 1.06 | Ambiguous | 0.12 | Likely Benign | 0.251 | Likely Benign | -4.94 | Deleterious | 0.995 | Probably Damaging | 0.767 | Possibly Damaging | 3.90 | Benign | 0.01 | Affected | 0.0909 | 0.5220 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.866T>G | M289R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of tools lean toward a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -11.090 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.28 | Likely Benign | 0.16 | Likely Benign | 1.01 | Destabilizing | 0.228 | Likely Benign | -2.84 | Deleterious | 0.989 | Probably Damaging | 0.767 | Possibly Damaging | 1.84 | Pathogenic | 0.08 | Tolerated | 0.1482 | 0.0828 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1495A>G | R499G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499G is listed in gnomAD (variant ID 6‑33438527‑A‑G) but has no ClinVar entry. Prediction tools that assess the variant’s effect on protein function overwhelmingly indicate a deleterious outcome: REVEL, FoldX‑MD (Rosetta component), Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic. Only FoldX (overall) and AlphaMissense‑Optimized report uncertain results, which are treated as unavailable evidence. No tool predicts a benign effect. High‑accuracy assessments specifically show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for R499G, and this conclusion is not contradicted by any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438527-A-G | 3 | 1.86e-6 | -9.960 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 1.55 | Ambiguous | 0.1 | 2.75 | Destabilizing | 2.15 | Destabilizing | 1.41 | Destabilizing | 0.681 | Likely Pathogenic | -4.50 | Deleterious | 0.958 | Probably Damaging | 0.769 | Possibly Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2888 | 0.1798 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.3533A>C | Y1178S 2D  AIThe SynGAP1 missense variant Y1178S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -1.440 | Likely Benign | 0.771 | Likely Pathogenic | Likely Benign | 0.329 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.769 | Possibly Damaging | 5.57 | Benign | 0.33 | Tolerated | 0.5225 | 0.1626 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.1012G>C | D338H 2D AIThe SynGAP1 missense variant D338H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to premPS, whereas the remaining 11 tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for D338H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -12.325 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 1.2 | 0.76 | Ambiguous | 1.04 | Ambiguous | 0.18 | Likely Benign | 0.515 | Likely Pathogenic | -4.42 | Deleterious | 0.966 | Probably Damaging | 0.770 | Possibly Damaging | 1.71 | Pathogenic | 0.01 | Affected | 0.1671 | 0.6654 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.3430T>G | L1144V 2D AIThe SynGAP1 missense variant L1144V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.025 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.227 | Likely Benign | -0.04 | Neutral | 0.952 | Possibly Damaging | 0.770 | Possibly Damaging | 5.43 | Benign | 0.70 | Tolerated | 0.1553 | 0.3297 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1964T>C | L655P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L655P is catalogued in gnomAD (ID 6‑33441223‑T‑C) but has no ClinVar entry. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, and FATHMM, whereas pathogenic calls are made by Rosetta, Foldetta, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are uncertain. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the majority of evidence points to a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | 6-33441223-T-C | 1 | 6.20e-7 | -9.771 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.33 | Ambiguous | 0.5 | 6.52 | Destabilizing | 3.93 | Destabilizing | 0.57 | Ambiguous | 0.126 | Likely Benign | -1.36 | Neutral | 0.981 | Probably Damaging | 0.772 | Possibly Damaging | 3.47 | Benign | 0.32 | Tolerated | 3.39 | 24 | 0.3598 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.2971G>A | G991R 2D AIThe SynGAP1 missense variant G991R is listed in ClinVar (ID 1029090.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443523‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | Conflicting | 3 | 6-33443523-G-A | 8 | 4.96e-6 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0956 | 0.4181 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2971G>C | G991R 2D AIThe SynGAP1 missense variant G991R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for G991R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0956 | 0.4181 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3529G>C | E1177Q 2D AIThe SynGAP1 missense variant E1177Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the evidence is mixed, with an equal split between benign and pathogenic calls; however, the consensus from the high‑accuracy tools leans toward benign. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.517 | Likely Benign | 0.812 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -0.95 | Neutral | 0.951 | Possibly Damaging | 0.772 | Possibly Damaging | 5.43 | Benign | 0.04 | Affected | 0.0712 | 0.4265 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.1219C>A | Q407K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools, FoldX and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is unavailable because FoldX is uncertain and Rosetta alone is benign. Overall, the majority of evidence points to a pathogenic impact for Q407K. This conclusion is not contradicted by ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -14.893 | Likely Pathogenic | 0.765 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.40 | Likely Benign | 0.93 | Ambiguous | 0.246 | Likely Benign | -3.42 | Deleterious | 0.863 | Possibly Damaging | 0.773 | Possibly Damaging | 3.96 | Benign | 0.07 | Tolerated | 0.1656 | 0.3504 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.2104C>A | Q702K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -8.750 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.02 | Likely Benign | 0.08 | Likely Benign | 0.224 | Likely Benign | -2.86 | Deleterious | 0.863 | Possibly Damaging | 0.773 | Possibly Damaging | 3.46 | Benign | 0.08 | Tolerated | 0.1346 | 0.2524 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||
| c.2261A>T | E754V 2D AIThe SynGAP1 missense variant E754V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions) and the high‑accuracy benign call suggest that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -6.147 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.157 | Likely Benign | -1.86 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.45 | Pathogenic | 0.28 | Tolerated | 0.0730 | 0.7417 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2407A>C | K803Q 2D AIThe SynGAP1 missense variant K803Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -2.792 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -2.01 | Neutral | 0.984 | Probably Damaging | 0.773 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.4810 | 0.1398 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.2419T>A | Y807N 2D  AIThe SynGAP1 missense variant Y807N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. ESM1b is uncertain. High‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, a protein‑folding stability approach that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -7.795 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.154 | Likely Benign | -4.01 | Deleterious | 0.934 | Possibly Damaging | 0.773 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.2274 | 0.0704 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.2419T>G | Y807D 2D  AIThe SynGAP1 missense variant Y807D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, while the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Uncertain calls come from ESM1b and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for Y807D, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -7.598 | In-Between | 0.862 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | -4.40 | Deleterious | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3944 | 0.0704 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.2545G>T | D849Y 2D  AIThe SynGAP1 missense variant D849Y has no ClinVar entry and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy tools further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the majority of reliable predictors and consensus analyses indicate a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.554191 | Binding | 0.319 | 0.813 | 0.500 | -6.200 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -1.92 | Neutral | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.0767 | 0.7690 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2995T>C | S999P 2D AIThe SynGAP1 missense variant S999P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S999P, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -2.279 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.05 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.65 | Benign | 0.04 | Affected | 0.1963 | 0.6268 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3386T>C | L1129P 2D AIThe SynGAP1 missense variant L1129P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | Uncertain | 2 | -2.991 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.432 | Likely Benign | 0.27 | Neutral | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 5.44 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3017 | 0.2231 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3769T>C | S1257P 2D AIThe SynGAP1 missense variant S1257P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; Foldetta results are unavailable. Overall, the majority of computational evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -11.985 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -2.54 | Deleterious | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1656 | 0.4519 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||
| c.3875T>C | L1292P 2D AISynGAP1 missense variant L1292P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑to‑2 split and is therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. With half the tools indicating benign and half indicating pathogenic, the overall computational evidence is ambiguous. Consequently, the variant is neither clearly benign nor pathogenic based on current predictions, and there is no ClinVar entry to contradict this uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -3.761 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -4.58 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 0.3855 | 0.1220 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3875T>G | L1292R 2D AIThe SynGAP1 missense variant L1292R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -4.249 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -4.34 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.1286 | 0.0849 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.100T>C | Y34H 2D  AIThe SynGAP1 missense variant Y34H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Y34H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -2.929 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.53 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.2630 | 0.1062 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.101A>C | Y34S 2D AIThe SynGAP1 missense variant Y34S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Y34S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -0.994 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.60 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.19 | Benign | 0.00 | Affected | 0.4760 | 0.2884 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.115T>C | Y39H 2D AIThe SynGAP1 missense variant Y39H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.166 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.08 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.2569 | 0.0843 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.116A>C | Y39S 2D AIThe SynGAP1 missense variant Y39S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for Y39S, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -1.634 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.57 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.4935 | 0.2649 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.1270G>T | V424F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V424F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or unavailable results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -10.947 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.99 | Ambiguous | 0.3 | -0.37 | Likely Benign | 0.81 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -3.66 | Deleterious | 0.995 | Probably Damaging | 0.775 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.0816 | 0.2094 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.131G>C | W44S 2D  AIThe SynGAP1 missense variant W44S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -5.113 | Likely Benign | 0.921 | Likely Pathogenic | Ambiguous | 0.275 | Likely Benign | -4.68 | Deleterious | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 3.16 | Benign | 0.00 | Affected | 0.4139 | 0.2371 | -2 | -3 | 0.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.134A>C | N45T 2D AIThe SynGAP1 missense variant N45T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -2.425 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.81 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 0.1642 | 0.8318 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.135C>A | N45K 2D AISynGAP1 missense variant N45K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus four pathogenic predictions, with two high‑accuracy tools supporting benign—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -1.711 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -0.58 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2409 | 0.6724 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.135C>G | N45K 2D AISynGAP1 missense variant N45K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus four pathogenic predictions, with two high‑accuracy tools supporting benign—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -1.711 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -0.58 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2409 | 0.6724 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.161A>C | N54T 2D AIThe SynGAP1 missense variant N54T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign impact, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -5.808 | Likely Benign | 0.386 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -0.47 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.1268 | 0.7498 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.162C>A | N54K 2D AIThe SynGAP1 missense variant N54K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 0.2010 | 0.5987 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.162C>G | N54K 2D AIThe SynGAP1 missense variant N54K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 0.2010 | 0.5987 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.181G>C | E61Q 2D AIThe SynGAP1 missense variant E61Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for E61Q, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -5.443 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.41 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.1344 | 0.5617 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.182A>G | E61G 2D AIThe SynGAP1 missense variant E61G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and the protein‑folding stability tool Foldetta is not available for this variant. Overall, the majority of evidence points to a benign effect. There is no ClinVar entry to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -5.574 | Likely Benign | 0.469 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.68 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 0.3593 | 0.4965 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.182A>T | E61V 2D AIThe SynGAP1 E61V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -5.723 | Likely Benign | 0.769 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.80 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.0803 | 0.6413 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.187G>C | E63Q 2D AIThe SynGAP1 missense variant E63Q is listed in ClinVar (ID 2132335.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | Uncertain | 1 | -4.038 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -0.85 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0970 | 0.6787 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.188A>G | E63G 2D AIThe SynGAP1 missense variant E63G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Overall, the majority of individual predictors and the SGM‑Consensus lean toward a benign interpretation, with no conflicting evidence from ClinVar. Thus, the variant is most likely benign based on current computational predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.450 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -2.24 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 0.2705 | 0.5786 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.188A>T | E63V 2D AIThe SynGAP1 E63V missense variant has no ClinVar record and is not present in gnomAD. Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized returns an Uncertain result, and no Foldetta stability data are available. Overall, the balance of evidence leans toward a benign effect, with several high‑confidence predictors supporting pathogenicity, leaving the assessment inconclusive. The predictions do not contradict any ClinVar status, as none is assigned. Based on the aggregate predictions, the variant is most likely benign, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.474807 | Uncertain | 0.494 | 0.739 | 0.125 | -3.588 | Likely Benign | 0.921 | Likely Pathogenic | Ambiguous | 0.143 | Likely Benign | -2.15 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.0559 | 0.7584 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.301C>A | H101N 2D  AIThe SynGAP1 missense variant H101N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of the benign‑predicted tools). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from the same set of benign‑predicted tools) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -3.598 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.49 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.1651 | 0.2994 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.301C>T | H101Y 2D  AIThe SynGAP1 missense variant H101Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H101Y, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -3.404 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.95 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.0862 | 0.4004 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.1894A>G | N632D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N632D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic effect, while SGM‑Consensus also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because the majority of evidence points to deleterious impact and there is no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -14.117 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 1.84 | Ambiguous | 0.4 | 1.50 | Ambiguous | 1.67 | Ambiguous | 1.09 | Destabilizing | 0.827 | Likely Pathogenic | -4.31 | Deleterious | 0.985 | Probably Damaging | 0.776 | Possibly Damaging | -1.53 | Pathogenic | 0.01 | Affected | 0.1791 | 0.3854 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1954T>A | F652I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability assessment is missing or inconclusive. Based on the consensus of the available tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -12.085 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.15 | Destabilizing | 0.1 | 3.40 | Destabilizing | 2.78 | Destabilizing | 1.40 | Destabilizing | 0.574 | Likely Pathogenic | -5.71 | Deleterious | 0.996 | Probably Damaging | 0.776 | Possibly Damaging | 3.06 | Benign | 0.00 | Affected | 0.1553 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1990T>G | L664V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic (3 pathogenic vs 1 benign). Foldetta’s stability prediction is uncertain. Overall, the majority of reliable tools predict a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -11.515 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 2.01 | Destabilizing | 0.1 | 1.13 | Ambiguous | 1.57 | Ambiguous | 1.37 | Destabilizing | 0.378 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.776 | Possibly Damaging | 2.91 | Benign | 0.01 | Affected | 0.0984 | 0.2628 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2629C>A | L877M 2D AIThe SynGAP1 missense variant L877M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the two polyPhen‑2 scores (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -6.266 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.55 | Neutral | 0.922 | Possibly Damaging | 0.776 | Possibly Damaging | 2.58 | Benign | 0.15 | Tolerated | 0.0813 | 0.3532 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.1171G>A | G391S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and FoldX. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact for G391S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -5.531 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 2.14 | Destabilizing | 0.6 | 1.01 | Ambiguous | 1.58 | Ambiguous | 0.06 | Likely Benign | 0.462 | Likely Benign | -0.54 | Neutral | 0.978 | Probably Damaging | 0.777 | Possibly Damaging | 1.33 | Pathogenic | 0.35 | Tolerated | 0.2820 | 0.5097 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2008C>A | L670M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L670M occurs in the GAP domain. ClinVar contains no entry for this variant, but it is present in gnomAD (ID 6‑33441267‑C‑A). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, Foldetta, and the SGM‑Consensus score (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; Rosetta gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | 6-33441267-C-A | 2 | 1.24e-6 | -9.438 | Likely Pathogenic | 0.125 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.0 | 0.70 | Ambiguous | 0.30 | Likely Benign | 0.06 | Likely Benign | 0.038 | Likely Benign | -0.16 | Neutral | 0.970 | Probably Damaging | 0.777 | Possibly Damaging | 3.40 | Benign | 0.25 | Tolerated | 3.39 | 27 | 0.0826 | 0.3849 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||
| c.2660C>A | P887H 2D AIThe SynGAP1 missense variant P887H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P887H, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.602269 | Binding | 0.348 | 0.925 | 0.500 | -4.900 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.71 | Neutral | 0.977 | Probably Damaging | 0.777 | Possibly Damaging | 2.73 | Benign | 0.13 | Tolerated | 0.1236 | 0.3275 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3157A>T | S1053C 2D AIThe SynGAP1 missense variant S1053C is catalogued in gnomAD (ID 6‑33443709‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The ESM1b score is uncertain, providing no clear direction. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the majority of reliable predictors classify S1053C as benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443709-A-T | -7.574 | In-Between | 0.095 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.61 | Neutral | 0.977 | Probably Damaging | 0.777 | Possibly Damaging | 5.30 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1675 | 0.5895 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3166G>T | G1056C 2D AIThe SynGAP1 missense variant G1056C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.974 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.432 | Likely Benign | -0.70 | Neutral | 0.994 | Probably Damaging | 0.777 | Possibly Damaging | 1.83 | Pathogenic | 0.06 | Tolerated | 0.1414 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3395C>G | S1132C 2D AIThe SynGAP1 missense variant S1132C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1132C, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -6.668 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.318 | Likely Benign | -1.76 | Neutral | 0.977 | Probably Damaging | 0.777 | Possibly Damaging | 5.39 | Benign | 0.06 | Tolerated | 0.1199 | 0.5888 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.334G>T | G112W 2D AIThe SynGAP1 missense variant G112W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic interpretation. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -6.382 | Likely Benign | 0.720 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -3.98 | Deleterious | 0.983 | Probably Damaging | 0.778 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.0631 | 0.4212 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.986G>A | R329H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329H is listed in ClinVar with an uncertain significance (ClinVar ID 2074400.0) and is present in gnomAD (ID 6‑33437891‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the balance of predictions favors a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests the variant is more likely deleterious. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | Uncertain | 1 | 6-33437891-G-A | 2 | 1.24e-6 | -10.154 | Likely Pathogenic | 0.769 | Likely Pathogenic | Likely Benign | 2.53 | Destabilizing | 0.7 | 0.71 | Ambiguous | 1.62 | Ambiguous | 0.82 | Ambiguous | 0.155 | Likely Benign | -3.17 | Deleterious | 0.995 | Probably Damaging | 0.778 | Possibly Damaging | 4.04 | Benign | 0.05 | Affected | 3.41 | 15 | 0.2955 | 0.1961 | 2 | 0 | 1.3 | -19.05 | 220.4 | 81.4 | 0.1 | 0.1 | 0.2 | 0.3 | Uncertain | The guanidinium group of Arg329, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces the negatively charged lipid bilayer surface. While the residue swap does not cause any apparent negative effects on the protein structure in the variant simulations, it could adversely affect the SynGAP-membrane association in reality. The positively charged Arg329 side chain forms hydrogen bonds with other loop residues (e.g., Ser371, Asp338) that are expected to dynamically interact with the membrane head group region. However, this phenomenon is beyond the scope of the solvent-only simulations to unravel. Notably, histidine can also be double protonated and positively charged, but this alternative protonation state was not considered in the variant simulations. | ||||||||||||||
| c.1761G>C | R587S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R587S is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; AlphaMissense‑Optimized is “Uncertain”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also “Uncertain.” Taken together, the preponderance of evidence points to a pathogenic impact for R587S. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | -12.264 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.84 | Ambiguous | 0.1 | 1.79 | Ambiguous | 1.32 | Ambiguous | 1.17 | Destabilizing | 0.508 | Likely Pathogenic | -4.84 | Deleterious | 0.990 | Probably Damaging | 0.779 | Possibly Damaging | -1.20 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 0.2852 | 0.4165 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||
| c.1761G>T | R587S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R587S missense variant is catalogued in gnomAD (ID 6‑33440813‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Uncertain results are reported by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized remains uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta likewise yields an uncertain stability change. Overall, the preponderance of evidence indicates that R587S is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | 6-33440813-G-T | 4 | 2.48e-6 | -12.264 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.84 | Ambiguous | 0.1 | 1.79 | Ambiguous | 1.32 | Ambiguous | 1.17 | Destabilizing | 0.508 | Likely Pathogenic | -4.84 | Deleterious | 0.990 | Probably Damaging | 0.779 | Possibly Damaging | -1.20 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 0.2852 | 0.4165 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||
| c.1946T>C | M649T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -11.916 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.2 | 3.45 | Destabilizing | 3.32 | Destabilizing | 1.92 | Destabilizing | 0.531 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.779 | Possibly Damaging | 3.35 | Benign | 0.00 | Affected | 0.1732 | 0.1615 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1370G>C | S457T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting likely pathogenic, and Foldetta predicting benign. Overall, the majority of high‑confidence tools lean toward a benign effect, and there is no conflict with the ClinVar status, which is currently unreported. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.772 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.13 | Likely Benign | 0.38 | Likely Benign | 0.273 | Likely Benign | -2.83 | Deleterious | 0.866 | Possibly Damaging | 0.780 | Possibly Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.1154 | 0.6487 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2041G>A | G681S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM, while those that predict a pathogenic outcome are SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of tools lean toward pathogenicity, but the presence of a benign prediction from AlphaMissense‑Optimized and an uncertain Foldetta score leaves the assessment inconclusive. No ClinVar entry exists, so there is no contradiction with clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -9.913 | Likely Pathogenic | 0.716 | Likely Pathogenic | Likely Benign | 2.11 | Destabilizing | 1.3 | -0.23 | Likely Benign | 0.94 | Ambiguous | 0.41 | Likely Benign | 0.483 | Likely Benign | -5.99 | Deleterious | 0.997 | Probably Damaging | 0.780 | Possibly Damaging | 3.45 | Benign | 0.08 | Tolerated | 0.2591 | 0.4584 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2199G>C | Q733H 2D AIThe SynGAP1 missense variant Q733H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.741 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -2.47 | Neutral | 0.990 | Probably Damaging | 0.780 | Possibly Damaging | 2.52 | Benign | 0.02 | Affected | 0.1341 | 0.2263 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2199G>T | Q733H 2D AIThe SynGAP1 missense variant Q733H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q733H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.741 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -2.47 | Neutral | 0.990 | Probably Damaging | 0.780 | Possibly Damaging | 2.52 | Benign | 0.02 | Affected | 0.1341 | 0.2263 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2393C>A | P798Q 2D AIThe SynGAP1 missense variant P798Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P798Q, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.944 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.53 | Neutral | 0.988 | Probably Damaging | 0.780 | Possibly Damaging | 4.25 | Benign | 0.00 | Affected | 0.1290 | 0.3864 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2393C>G | P798R 2D AIThe SynGAP1 missense variant P798R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P798R, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.232 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.83 | Neutral | 0.976 | Probably Damaging | 0.780 | Possibly Damaging | 4.25 | Benign | 0.00 | Affected | 0.1397 | 0.2840 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.206T>A | I69N 2D  AIThe SynGAP1 missense variant I69N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.466129 | Uncertain | 0.437 | 0.786 | 0.375 | -3.220 | Likely Benign | 0.631 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -0.90 | Neutral | 0.943 | Possibly Damaging | 0.781 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0859 | 0.0412 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.566C>T | P189L 2D AIThe SynGAP1 missense variant P189L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic classification, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -10.132 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | -7.28 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 4.04 | Benign | 0.17 | Tolerated | 0.2283 | 0.7378 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.608A>T | D203V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools and the SGM Consensus lean toward a pathogenic interpretation, whereas two high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest benign. Because ClinVar contains no entry for this variant, there is no contradiction between the predictions and existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -10.660 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.32 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.38 | Likely Benign | 0.05 | Likely Benign | 0.289 | Likely Benign | -4.07 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 3.98 | Benign | 0.02 | Affected | 0.0534 | 0.4084 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||
| c.755C>T | P252L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign are premPS and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute to the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.181 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.93 | Ambiguous | 0.0 | 1.56 | Ambiguous | 1.25 | Ambiguous | 0.47 | Likely Benign | 0.794 | Likely Pathogenic | -9.19 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.2027 | 0.6475 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.2753C>T | A918V 2D AIThe SynGAP1 missense variant A918V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443305‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability prediction is not available. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 3 | 6-33443305-C-T | 2 | 1.24e-6 | -3.684 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -1.61 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1226 | 0.5586 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.2929G>A | A977T 2D AIThe SynGAP1 missense variant A977T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -3.814 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.84 | Neutral | 0.965 | Probably Damaging | 0.782 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 0.2155 | 0.6185 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3025G>C | E1009Q 2D AIThe SynGAP1 missense variant E1009Q is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33443577‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | 6-33443577-G-C | 1 | 6.20e-7 | -3.423 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -1.65 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1577 | 0.7242 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3737A>C | K1246T 2D AIThe SynGAP1 missense variant K1246T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification for K1246T, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -1.970 | Likely Benign | 0.263 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -2.19 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 0.2032 | 0.2065 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.989A>G | D330G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two predictors (AlphaMissense‑Optimized and premPS) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that D330G is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -13.064 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 2.69 | Destabilizing | 0.2 | 2.17 | Destabilizing | 2.43 | Destabilizing | 0.63 | Ambiguous | 0.373 | Likely Benign | -5.03 | Deleterious | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 0.94 | Pathogenic | 0.01 | Affected | 0.3935 | 0.5015 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2945A>C | Y982S 2D AIThe SynGAP1 missense variant Y982S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus as Likely Benign, AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.966717 | Binding | 0.272 | 0.895 | 0.625 | -2.919 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.131 | Likely Benign | -1.04 | Neutral | 0.965 | Probably Damaging | 0.783 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 0.4556 | 0.1883 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3028T>A | F1010I 2D AIThe SynGAP1 missense variant F1010I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -3.726 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.74 | Neutral | 0.980 | Probably Damaging | 0.783 | Possibly Damaging | 2.57 | Benign | 0.05 | Affected | 0.2405 | 0.2464 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3740G>C | R1247T 2D  AIThe SynGAP1 missense variant R1247T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. No Foldetta stability result is available. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.736850 | Disordered | 0.374141 | Uncertain | 0.875 | 0.557 | 0.625 | -6.302 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | -4.79 | Deleterious | 0.980 | Probably Damaging | 0.783 | Possibly Damaging | 1.71 | Pathogenic | 0.00 | Affected | 0.1543 | 0.2403 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||
| c.2957A>G | E986G 2D AIThe SynGAP1 missense variant E986G is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas seven tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with the ClinVar status, which currently contains no classification for E986G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -5.584 | Likely Benign | 0.834 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -3.14 | Deleterious | 0.924 | Possibly Damaging | 0.784 | Possibly Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.2866 | 0.6225 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.180T>A | D60E 2D  AIThe SynGAP1 D60E missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -3.818 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.90 | Neutral | 0.643 | Possibly Damaging | 0.785 | Possibly Damaging | 4.05 | Benign | 0.00 | Affected | 0.1342 | 0.7869 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.180T>G | D60E 2D AIThe SynGAP1 D60E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -3.818 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.90 | Neutral | 0.643 | Possibly Damaging | 0.785 | Possibly Damaging | 4.05 | Benign | 0.00 | Affected | 0.1342 | 0.7869 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3991A>C | I1331L 2D AIThe SynGAP1 missense variant I1331L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively classify the variant as likely benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -2.450 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -1.04 | Neutral | 0.762 | Possibly Damaging | 0.785 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0.0752 | 0.3616 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3991A>G | I1331V 2D  AIThe SynGAP1 missense variant I1331V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -2.799 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | -0.51 | Neutral | 0.581 | Possibly Damaging | 0.785 | Possibly Damaging | 3.59 | Benign | 0.00 | Affected | 0.1091 | 0.3074 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1792C>G | L598V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L598V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | Uncertain | 1 | -10.002 | Likely Pathogenic | 0.578 | Likely Pathogenic | Likely Benign | 1.89 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.74 | Ambiguous | 1.01 | Destabilizing | 0.221 | Likely Benign | -2.92 | Deleterious | 0.944 | Possibly Damaging | 0.786 | Possibly Damaging | 3.21 | Benign | 0.02 | Affected | 3.37 | 35 | 0.1082 | 0.1795 | 2 | 1 | 0.4 | -14.03 | 218.4 | 29.6 | 0.0 | 0.0 | 0.8 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu598, located on an α helix (res. Glu582-Met603), packs hydrophobically with other hydrophobic residues in the inter-helix space (e.g., Ile602, Phe594, Ile510).In the variant simulations, Val598, which has similar size and physicochemical properties to leucine, resides in the inter-helix hydrophobic space in a similar manner to Leu598 in the WT. This causes no negative effects on the protein structure. | ||||||||||||||||
| c.2314T>C | F772L 2D  AIThe SynGAP1 missense variant F772L is listed in gnomAD (6‑33442472‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442472-T-C | 1 | 1.28e-6 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.161 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.2315T>A | F772Y 2D  AIThe SynGAP1 missense variant F772Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.657 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.54 | Neutral | 0.705 | Possibly Damaging | 0.786 | Possibly Damaging | 4.17 | Benign | 0.35 | Tolerated | 0.1058 | 0.1892 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2316C>A | F772L 2D AIThe SynGAP1 missense variant F772L is catalogued in gnomAD (ID 6‑33442474‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence indicates that F772L is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442474-C-A | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.2316C>G | F772L 2D AIThe SynGAP1 missense variant F772L has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability data are available, so it is treated as unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.2572A>G | S858G 2D AIThe SynGAP1 missense variant S858G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumVar indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -2.181 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.18 | Neutral | 0.259 | Benign | 0.786 | Possibly Damaging | 4.13 | Benign | 0.11 | Tolerated | 0.3084 | 0.5116 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2573G>C | S858T 2D AIThe SynGAP1 missense variant S858T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumVar predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that S858T is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -4.960 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.92 | Neutral | 0.259 | Benign | 0.786 | Possibly Damaging | 4.14 | Benign | 0.06 | Tolerated | 0.1660 | 0.6489 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2705C>A | A902D 2D AIThe SynGAP1 missense variant A902D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -5.273 | Likely Benign | 0.823 | Likely Pathogenic | Ambiguous | 0.101 | Likely Benign | -1.21 | Neutral | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 2.59 | Benign | 0.00 | Affected | 0.1653 | 0.1609 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3119G>A | G1040D 2D AIThe SynGAP1 missense variant G1040D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only ESM1b, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. The high‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence indicates that G1040D is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -4.154 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.761 | Likely Pathogenic | -2.82 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | -0.74 | Pathogenic | 0.00 | Affected | 0.1677 | 0.2042 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3122C>G | P1041R 2D AIThe SynGAP1 missense variant P1041R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The AlphaMissense‑Default result is uncertain, and no Foldetta stability data are available, so these are treated as unavailable. Overall, six tools support a benign classification while three support pathogenicity, and the high‑accuracy AlphaMissense‑Optimized and SGM Consensus both predict benign. Therefore, the variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.808 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.443 | Likely Benign | -3.33 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 5.46 | Benign | 0.07 | Tolerated | 0.1401 | 0.4292 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3143G>T | G1048V 2D AIThe SynGAP1 missense variant G1048V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -6.108 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.520 | Likely Pathogenic | -0.59 | Neutral | 0.958 | Probably Damaging | 0.787 | Possibly Damaging | 2.54 | Benign | 0.11 | Tolerated | 0.1312 | 0.3688 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3229A>C | T1077P 2D AIThe SynGAP1 missense variant T1077P is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence shows AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of predictions and the high‑accuracy consensus point to a benign impact. This conclusion is not contradicted by ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -2.436 | Likely Benign | 0.345 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -0.91 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.16 | Benign | 0.04 | Affected | 0.1876 | 0.4788 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>T | T1077I 2D AIThe SynGAP1 missense variant T1077I is listed in gnomAD (ID 6‑33443782‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, SIFT, ESM1b, FATHMM) and pathogenic predictions (PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, AlphaMissense‑Default). The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict (3 benign vs. 1 pathogenic). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this residue. Taken together, the majority of evidence points toward a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, and there is no contradiction with existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443782-C-T | 1 | 6.25e-7 | -4.710 | Likely Benign | 0.919 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.11 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.19 | Benign | 0.33 | Tolerated | 3.77 | 5 | 0.1135 | 0.5870 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.3307C>T | R1103C 2D  AISynGAP1 missense variant R1103C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443859‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized reports a benign outcome, while Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443859-C-T | 6 | 3.92e-6 | -2.440 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -3.01 | Deleterious | 0.996 | Probably Damaging | 0.787 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3376 | 0.4121 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.3547T>G | Y1183D 2D AISynGAP1 missense variant Y1183D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, a majority‑vote model of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts the variant as likely benign. High‑accuracy assessments further indicate AlphaMissense‑Optimized as pathogenic, whereas Foldetta (FoldX‑MD/Rosetta stability analysis) is not available for this residue. Overall, the balance of evidence leans toward a benign effect, and this assessment does not conflict with ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.718 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.10 | Neutral | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 2.83 | Benign | 0.61 | Tolerated | 0.4602 | 0.0243 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.3907G>C | G1303R 2D AIThe SynGAP1 missense variant G1303R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic effect, whereas REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign outcome. Grouping by consensus, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN—also reports a likely benign status. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a benign effect for G1303R, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.093 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.364 | Likely Benign | -1.84 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 2.81 | Benign | 0.05 | Affected | 0.1024 | 0.3596 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2719A>G | S907G 2D AIThe SynGAP1 missense variant S907G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.018 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.23 | Neutral | 0.942 | Possibly Damaging | 0.788 | Possibly Damaging | 2.63 | Benign | 0.04 | Affected | 0.2625 | 0.5134 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.272A>T | E91V 2D AIThe SynGAP1 E91V missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Overall, the evidence is mixed, but the consensus of several independent benign predictors and the SGM‑Consensus lean toward a benign interpretation. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | -3.697 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -2.16 | Neutral | 0.947 | Possibly Damaging | 0.788 | Possibly Damaging | 3.84 | Benign | 0.00 | Affected | 0.0940 | 0.7457 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.290A>T | E97V 2D AIThe SynGAP1 missense variant E97V is listed in gnomAD (ID 6‑33425898‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data is missing. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.609018 | Binding | 0.340 | 0.867 | 0.625 | 6-33425898-A-T | 1 | 6.20e-7 | -3.743 | Likely Benign | 0.514 | Ambiguous | Likely Benign | 0.124 | Likely Benign | -1.17 | Neutral | 0.947 | Possibly Damaging | 0.788 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1015 | 0.8155 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||
| c.1870A>T | T624S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T624S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -13.314 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | -0.10 | Likely Benign | 0.1 | 0.95 | Ambiguous | 0.43 | Likely Benign | 0.69 | Ambiguous | 0.761 | Likely Pathogenic | -3.93 | Deleterious | 0.826 | Possibly Damaging | 0.789 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 0.2326 | 0.2813 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1871C>G | T624S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T624S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -13.314 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | -0.10 | Likely Benign | 0.1 | 0.95 | Ambiguous | 0.43 | Likely Benign | 0.69 | Ambiguous | 0.734 | Likely Pathogenic | -3.93 | Deleterious | 0.826 | Possibly Damaging | 0.789 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 0.2326 | 0.2813 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2110A>T | S704C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based tools such as FoldX, Rosetta, and premPS also return uncertain results. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -10.438 | Likely Pathogenic | 0.423 | Ambiguous | Likely Benign | 1.56 | Ambiguous | 0.1 | 0.98 | Ambiguous | 1.27 | Ambiguous | 0.52 | Ambiguous | 0.251 | Likely Benign | -3.52 | Deleterious | 0.997 | Probably Damaging | 0.789 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.0789 | 0.4612 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.3789T>G | I1263M 2D AIThe SynGAP1 missense variant I1263M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). High‑accuracy methods are not available: AlphaMissense‑Optimized is benign, but AlphaMissense‑Default is pathogenic; Foldetta results are missing. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -2.839 | Likely Benign | 0.701 | Likely Pathogenic | Likely Benign | 0.291 | Likely Benign | -2.49 | Neutral | 0.968 | Probably Damaging | 0.789 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0654 | 0.2170 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.1937T>A | L646Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L646Q lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.735 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.1 | 3.04 | Destabilizing | 3.14 | Destabilizing | 2.12 | Destabilizing | 0.462 | Likely Benign | -2.78 | Deleterious | 0.994 | Probably Damaging | 0.790 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.2090 | 0.1963 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1999A>T | I667F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I667F missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls are limited to FATHMM, while the remaining 11 predictors—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -14.389 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 7.55 | Destabilizing | 0.3 | 1.80 | Ambiguous | 4.68 | Destabilizing | 0.86 | Ambiguous | 0.569 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 2.96 | Benign | 0.00 | Affected | 0.0668 | 0.2648 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2002T>C | S668P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668P has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the only benign predictor, while the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic or likely pathogenic. The premPS score is uncertain and therefore not used as evidence. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -13.452 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.40 | Destabilizing | 1.1 | 10.90 | Destabilizing | 8.65 | Destabilizing | 0.61 | Ambiguous | 0.612 | Likely Pathogenic | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.16 | Benign | 0.02 | Affected | 0.1979 | 0.5137 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.2068T>C | S690P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, a conclusion that does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | Uncertain | 1 | -14.568 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.3 | 4.40 | Destabilizing | 4.62 | Destabilizing | 1.42 | Destabilizing | 0.431 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.44 | Benign | 0.01 | Affected | 3.42 | 17 | 0.1787 | 0.4050 | 1 | -1 | -0.8 | 10.04 | 207.5 | 15.1 | 0.1 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl side chain of Ser690, located in an α-helix (res. Leu696-Leu685), forms a hydrogen bond with the backbone carbonyl group of Ser410 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399). In the variant simulations, the pyrrolidine side chain of Pro690 cannot form hydrogen bonds with the C2 domain residue, resulting in the loss of this inter-domain connection. Additionally, prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Gly686, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.1382C>A | A461D 2D AIThe SynGAP1 missense variant A461D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A461D is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -14.918 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.89 | Ambiguous | 1.1 | 2.18 | Destabilizing | 1.54 | Ambiguous | 1.09 | Destabilizing | 0.477 | Likely Benign | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.792 | Possibly Damaging | 3.32 | Benign | 0.01 | Affected | 0.1533 | 0.2016 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.2210A>G | Q737R 2D  AIThe SynGAP1 missense variant Q737R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for Q737R, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -4.524 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.02 | Neutral | 0.986 | Probably Damaging | 0.793 | Possibly Damaging | 2.74 | Benign | 0.06 | Tolerated | 0.1688 | 0.1852 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2768T>A | I923N 2D AIThe SynGAP1 missense variant I923N (ClinVar ID 647043.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” because the majority of its constituent tools (three benign, one pathogenic) favor a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, and the Foldetta stability analysis is unavailable. Overall, the collective predictions point to a benign impact, which does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.964857 | Binding | 0.292 | 0.852 | 0.250 | Uncertain | 1 | -0.733 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -1.16 | Neutral | 0.991 | Probably Damaging | 0.793 | Possibly Damaging | 2.70 | Benign | 0.13 | Tolerated | 3.77 | 5 | 0.1164 | 0.1073 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.1016A>C | K339T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools are split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further highlight this discordance: the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect, whereas Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. AlphaMissense‑Optimized returned an uncertain result and is treated as unavailable. Overall, the majority of robust predictors lean toward pathogenicity, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -10.061 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.32 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.21 | Likely Benign | -0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.73 | Deleterious | 0.991 | Probably Damaging | 0.795 | Possibly Damaging | 1.94 | Pathogenic | 0.10 | Tolerated | 0.1900 | 0.3020 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1141G>A | G381R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381R is not reported in ClinVar and is present in gnomAD (ID 6‑33438046‑G‑A). Prediction tools that classify it as benign include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic impact for G381R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-A | -8.990 | Likely Pathogenic | 0.652 | Likely Pathogenic | Likely Benign | 5.60 | Destabilizing | 0.9 | 2.80 | Destabilizing | 4.20 | Destabilizing | 0.20 | Likely Benign | 0.589 | Likely Pathogenic | -0.82 | Neutral | 0.985 | Probably Damaging | 0.795 | Possibly Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 9 | 0.1339 | 0.3945 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||
| c.1141G>C | G381R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G381R is catalogued in gnomAD (ID 6‑33438046‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence indicates a pathogenic impact for G381R, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-C | 2 | 1.25e-6 | -8.990 | Likely Pathogenic | 0.652 | Likely Pathogenic | Likely Benign | 5.60 | Destabilizing | 0.9 | 2.80 | Destabilizing | 4.20 | Destabilizing | 0.20 | Likely Benign | 0.589 | Likely Pathogenic | -0.82 | Neutral | 0.985 | Probably Damaging | 0.795 | Possibly Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 9 | 0.1339 | 0.3945 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.1633A>C | M545L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545L is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SIFT, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -7.163 | In-Between | 0.914 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.1 | 0.26 | Likely Benign | 0.16 | Likely Benign | 0.79 | Ambiguous | 0.638 | Likely Pathogenic | -2.72 | Deleterious | 0.732 | Possibly Damaging | 0.795 | Possibly Damaging | -1.26 | Pathogenic | 0.40 | Tolerated | 0.1239 | 0.2802 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1633A>T | M545L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545L has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, seven tools predict pathogenicity versus four predicting benign, with three uncertain. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -7.163 | In-Between | 0.914 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.1 | 0.26 | Likely Benign | 0.16 | Likely Benign | 0.79 | Ambiguous | 0.639 | Likely Pathogenic | -2.72 | Deleterious | 0.732 | Possibly Damaging | 0.795 | Possibly Damaging | -1.26 | Pathogenic | 0.40 | Tolerated | 0.1239 | 0.2802 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.629A>C | H210P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.634 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.5 | 2.80 | Destabilizing | 2.53 | Destabilizing | 1.00 | Destabilizing | 0.512 | Likely Pathogenic | -8.55 | Deleterious | 0.989 | Probably Damaging | 0.795 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1805 | 0.3175 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.728T>G | I243S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -14.097 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.22 | Destabilizing | 2.37 | Destabilizing | 1.71 | Destabilizing | 0.802 | Likely Pathogenic | -3.55 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 0.2658 | 0.0600 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.740A>C | Q247P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; premPS is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -14.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.43 | Destabilizing | 0.2 | 7.83 | Destabilizing | 5.63 | Destabilizing | 0.81 | Ambiguous | 0.770 | Likely Pathogenic | -3.56 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.69 | Benign | 0.02 | Affected | 0.1768 | 0.3631 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1034T>G | L345R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L345R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic prediction. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -10.325 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.66 | Ambiguous | 1.31 | Ambiguous | 1.28 | Destabilizing | 0.247 | Likely Benign | -3.98 | Deleterious | 0.993 | Probably Damaging | 0.796 | Possibly Damaging | 1.81 | Pathogenic | 0.04 | Affected | 0.1140 | 0.0685 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2272T>G | Y758D 2D AIThe SynGAP1 missense variant Y758D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.688 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -1.89 | Neutral | 0.973 | Probably Damaging | 0.796 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | 0.4647 | 0.0331 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2641T>A | L881M 2D AIThe SynGAP1 missense variant L881M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -4.419 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.31 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.49 | Pathogenic | 0.03 | Affected | 0.0807 | 0.3997 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2679G>C | Q893H 2D AIThe SynGAP1 missense variant Q893H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q893H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.783 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.1708 | 0.3879 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2679G>T | Q893H 2D AIThe SynGAP1 missense variant Q893H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q893H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.783 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.1708 | 0.3879 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>G | S955C 2D AIThe SynGAP1 missense variant S955C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (5 pathogenic vs. 4 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -8.675 | Likely Pathogenic | 0.117 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.48 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.1741 | 0.5470 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3074A>C | Q1025P 2D AIThe SynGAP1 missense variant Q1025P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -2.151 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -1.22 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.72 | Benign | 0.11 | Tolerated | 0.2211 | 0.5196 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3079A>T | N1027Y 2D  AIThe SynGAP1 missense variant N1027Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.799 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.074 | Likely Benign | -2.15 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.0611 | 0.6133 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3218C>A | S1073Y 2D AIThe SynGAP1 missense change S1073Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -6.768 | Likely Benign | 0.752 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -2.43 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0.0977 | 0.5684 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3218C>T | S1073F 2D AIThe SynGAP1 missense variant S1073F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -6.783 | Likely Benign | 0.836 | Likely Pathogenic | Ambiguous | 0.161 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0.0952 | 0.5957 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3260C>A | S1087Y 2D AIThe SynGAP1 missense variant S1087Y is catalogued in gnomAD (ID 6‑33443812‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-A | -4.194 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.41 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0671 | 0.5845 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.3260C>T | S1087F 2D AISynGAP1 missense variant S1087F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of reliable predictors and the two high‑accuracy tools suggest a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | Uncertain | 1 | -3.843 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -2.75 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0645 | 0.6029 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.3295T>C | Y1099H 2D AIThe SynGAP1 missense variant Y1099H is reported in gnomAD (variant ID 6-33443847‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443847-T-C | 1 | 6.49e-7 | -3.620 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.50 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.76 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2453 | 0.0735 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||
| c.3321G>C | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>T | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3389A>T | K1130M 2D AIThe SynGAP1 K1130M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for K1130M. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.844 | Likely Benign | 0.858 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | -1.62 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | 0.1703 | 0.4407 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3802C>A | L1268M 2D AIThe SynGAP1 missense variant L1268M is reported in gnomAD (ID 6‑33447850‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is not available. Overall, the preponderance of evidence from multiple in silico predictors and consensus methods indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | 6-33447850-C-A | -4.689 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.07 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.67 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.0627 | 0.2297 | 2 | 4 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3851T>A | L1284Q 2D AIThe SynGAP1 missense variant L1284Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.730 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -2.80 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.1065 | 0.0488 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3869G>T | R1290M 2D AIThe SynGAP1 missense variant R1290M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.661 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.143 | Likely Benign | -3.47 | Deleterious | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.1059 | 0.2899 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.461G>T | S154I 2D AIThe SynGAP1 missense variant S154I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not provided and is treated as unavailable. High‑accuracy predictions therefore indicate a benign outcome (AlphaMissense‑Optimized) with no decisive evidence from SGM Consensus or Foldetta. Overall, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -10.061 | Likely Pathogenic | 0.665 | Likely Pathogenic | Likely Benign | 0.105 | Likely Benign | -2.24 | Neutral | 0.990 | Probably Damaging | 0.797 | Possibly Damaging | 4.03 | Benign | 0.07 | Tolerated | 0.0953 | 0.5123 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3154G>A | G1052R 2D AISynGAP1 missense variant G1052R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status but provides additional support toward a likely benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | Uncertain | 1 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3154G>C | G1052R 2D AIThe SynGAP1 missense variant G1052R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3280T>C | S1094P 2D AIThe SynGAP1 missense variant S1094P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1094P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -2.430 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.31 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.46 | Pathogenic | 0.13 | Tolerated | 0.2322 | 0.6099 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3353G>T | S1118I 2D AIThe SynGAP1 missense variant S1118I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -5.710 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.309 | Likely Benign | -1.09 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 5.16 | Benign | 0.01 | Affected | 0.1486 | 0.4580 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3446C>A | P1149Q 2D AIThe SynGAP1 missense variant P1149Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -4.235 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -1.48 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.1515 | 0.4580 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.729T>G | I243M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243M has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign”; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -4.305 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.13 | Likely Benign | -0.01 | Likely Benign | 0.474 | Likely Benign | 0.58 | Neutral | 0.985 | Probably Damaging | 0.798 | Possibly Damaging | 5.61 | Benign | 0.94 | Tolerated | 0.0553 | 0.2200 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.2204G>C | S735T 2D AIThe SynGAP1 missense variant S735T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -5.340 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.03 | Neutral | 0.980 | Probably Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.46 | Tolerated | 0.1464 | 0.5321 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>G | S816A 2D AIThe SynGAP1 missense variant S816A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -4.543 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.07 | Neutral | 0.953 | Possibly Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.59 | Tolerated | 0.5307 | 0.4532 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3079A>C | N1027H 2D  AIThe SynGAP1 missense variant N1027H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy tools, indicate that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -4.185 | Likely Benign | 0.193 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.44 | Neutral | 0.970 | Probably Damaging | 0.799 | Possibly Damaging | 2.74 | Benign | 0.07 | Tolerated | 0.1345 | 0.7176 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3904T>A | L1302M 2D AIThe SynGAP1 missense variant L1302M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -5.246 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -1.34 | Neutral | 0.960 | Probably Damaging | 0.799 | Possibly Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.0929 | 0.3439 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.1847A>G | D616G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results—FoldX, AlphaMissense‑Default, and Foldetta—are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the predictions are split evenly between benign and pathogenic, with no clear consensus. Thus, the variant is most likely of uncertain significance; it does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -10.310 | Likely Pathogenic | 0.547 | Ambiguous | Likely Benign | 1.48 | Ambiguous | 0.1 | 2.13 | Destabilizing | 1.81 | Ambiguous | 0.49 | Likely Benign | 0.144 | Likely Benign | -5.60 | Deleterious | 0.985 | Probably Damaging | 0.800 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.3496 | 0.4386 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.1242G>A | M414I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 M414I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, more tools (five) predict pathogenicity than benign (four), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | 0.265 | Likely Benign | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 0.1168 | 0.3161 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1242G>C | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain, so these results are treated as unavailable. Overall, the majority of evaluated tools (5 pathogenic vs 4 benign) and the single high‑accuracy pathogenic prediction support a likely pathogenic classification. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | 0.265 | Likely Benign | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 0.1168 | 0.3161 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1242G>T | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain, so these results are treated as unavailable. Overall, the majority of evaluated tools (5 pathogenic vs 4 benign) and the single high‑accuracy pathogenic prediction support a likely pathogenic classification. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | 0.265 | Likely Benign | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 0.1168 | 0.3161 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.2390C>A | P797Q 2D AIThe SynGAP1 missense variant P797Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.926919 | Disordered | 0.449970 | Uncertain | 0.561 | 0.902 | 0.875 | -6.201 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.04 | Neutral | 0.940 | Possibly Damaging | 0.801 | Possibly Damaging | 4.23 | Benign | 0.15 | Tolerated | 0.1636 | 0.4787 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2606T>A | L869Q 2D AIThe SynGAP1 missense variant L869Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.925 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.57 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.60 | Benign | 0.06 | Tolerated | 0.0977 | 0.1203 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2606T>G | L869R 2D AIThe SynGAP1 missense variant L869R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.546 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.60 | Benign | 0.29 | Tolerated | 0.1162 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2672T>G | L891R 2D AIThe SynGAP1 missense variant L891R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and the protein‑folding stability tool Foldetta has no available result for this variant. Based on the aggregate evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.505861 | Binding | 0.305 | 0.923 | 0.750 | -4.120 | Likely Benign | 0.419 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.83 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.65 | Benign | 0.01 | Affected | 0.1233 | 0.0863 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2811T>A | D937E 2D AIThe SynGAP1 missense variant D937E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -3.342 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.07 | Neutral | 0.990 | Probably Damaging | 0.801 | Possibly Damaging | 2.76 | Benign | 0.15 | Tolerated | 0.2524 | 0.6915 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2811T>G | D937E 2D AIThe SynGAP1 D937E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the preponderance of benign predictions and the consensus from high‑accuracy methods, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -3.342 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.07 | Neutral | 0.990 | Probably Damaging | 0.801 | Possibly Damaging | 2.76 | Benign | 0.15 | Tolerated | 0.2524 | 0.6915 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3064C>T | L1022F 2D AIThe SynGAP1 missense variant L1022F is reported in gnomAD (variant ID 6‑33443616‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | 6-33443616-C-T | 2 | 1.24e-6 | -5.035 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.84 | Neutral | 0.971 | Probably Damaging | 0.801 | Possibly Damaging | 2.51 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.0730 | 0.4231 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||
| c.3196C>G | P1066A 2D AIThe SynGAP1 missense variant P1066A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -4.856 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -2.35 | Neutral | 0.972 | Probably Damaging | 0.802 | Possibly Damaging | 2.78 | Benign | 0.00 | Affected | 0.3228 | 0.6042 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2720G>A | S907N 2D AIThe SynGAP1 missense variant S907N is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority‑vote SGM‑Consensus also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy evaluations further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, with no Foldetta data to contradict this. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -4.520 | Likely Benign | 0.430 | Ambiguous | Likely Benign | 0.140 | Likely Benign | -0.26 | Neutral | 0.951 | Possibly Damaging | 0.803 | Possibly Damaging | 2.66 | Benign | 0.08 | Tolerated | 0.1312 | 0.4585 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.514C>T | R172W 2D AIThe SynGAP1 missense variant R172W is listed in ClinVar (ID 996892.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33435156‑C‑T). Prediction tools that agree on a benign effect include REVEL and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. High‑accuracy assessments therefore indicate a likely pathogenic outcome (SGM‑Consensus) with no definitive stabilizing‑folding evidence. Overall, the majority of computational predictions support a pathogenic classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | Uncertain | 2 | 6-33435156-C-T | 9 | 5.58e-6 | -10.258 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -3.61 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1071 | 0.4065 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.700C>T | R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | Uncertain | 1 | 6-33435551-C-T | 3 | 1.86e-6 | -12.625 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.96 | Ambiguous | 0.3 | 0.69 | Ambiguous | 0.83 | Ambiguous | 0.13 | Likely Benign | 0.805 | Likely Pathogenic | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 5.76 | Benign | 0.01 | Affected | 3.40 | 14 | 0.1302 | 0.4035 | 2 | -3 | 3.6 | 30.03 | 262.8 | 39.6 | -0.1 | 0.0 | -0.2 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions. | |||||||||||||
| c.197C>G | P66R 2D AIThe SynGAP1 missense variant P66R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the majority of evidence points toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -2.708 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -2.23 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.1636 | 0.3928 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2012A>C | D671A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671A missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with seven tools supporting pathogenicity versus four supporting benignity. This conclusion does not conflict with ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.709 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.1 | 0.79 | Ambiguous | 0.52 | Ambiguous | 0.10 | Likely Benign | 0.245 | Likely Benign | -5.08 | Deleterious | 0.980 | Probably Damaging | 0.804 | Possibly Damaging | 3.34 | Benign | 0.03 | Affected | 0.4056 | 0.5895 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.59C>G | P20R 2D AIThe SynGAP1 missense variant P20R is listed in ClinVar (ID 566521.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | Uncertain | 1 | -3.548 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -0.15 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1509 | 0.3272 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.68A>T | D23V 2D AIThe SynGAP1 D23V missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta predictions are not provided. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.244 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.137 | Likely Benign | -2.72 | Deleterious | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 3.48 | Benign | 0.00 | Affected | 0.1515 | 0.8367 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.1958T>G | L653R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L653R lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -16.078 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.92 | Destabilizing | 1.1 | 5.84 | Destabilizing | 6.38 | Destabilizing | 2.55 | Destabilizing | 0.649 | Likely Pathogenic | -5.75 | Deleterious | 0.997 | Probably Damaging | 0.806 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1501 | 0.0805 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2095G>A | V699M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V699M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441354‑G‑A). Across in silico predictors, benign calls are made by REVEL, Rosetta, Foldetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Default) are noted but not used as evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports benign stability. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the ClinVar uncertain status but provides a stronger leaning toward benignity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | Uncertain | 2 | 6-33441354-G-A | 8 | 4.96e-6 | -8.869 | Likely Pathogenic | 0.484 | Ambiguous | Likely Benign | -0.58 | Ambiguous | 0.1 | 0.29 | Likely Benign | -0.15 | Likely Benign | 0.96 | Ambiguous | 0.276 | Likely Benign | -2.18 | Neutral | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.37 | Benign | 0.03 | Affected | 3.47 | 10 | 0.0734 | 0.3071 | 2 | 1 | -2.3 | 32.06 | 257.8 | -47.2 | 0.0 | 0.0 | 0.9 | 0.1 | X | Potentially Benign | The isopropyl side chain of Val699, located on an α-helix (res. Leu685-Gln702), packs against hydrophobic residues (e.g., Leu703, Leu696, Leu435, Leu439) in the inter-helix space. In the variant simulations, the thioether side chain of Met699 has similar physicochemical properties to Val699 in the WT, and thus, it is able to maintain similar interactions. Consequently, the mutation causes no apparent changes in the structure. | ||||||||||||||
| c.2107C>T | L703F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta remains unavailable. Overall, the majority of reliable predictions lean toward pathogenicity, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -10.929 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.03 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.81 | Ambiguous | 0.50 | Likely Benign | 0.247 | Likely Benign | -3.25 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.12 | Benign | 0.00 | Affected | 0.0600 | 0.2555 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2108T>G | L703R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) all classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. The preponderance of pathogenic predictions, together with the high‑accuracy tools’ positive results, suggests that L703R is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -13.244 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 2.85 | Destabilizing | 0.0 | 3.74 | Destabilizing | 3.30 | Destabilizing | 1.79 | Destabilizing | 0.459 | Likely Benign | -4.92 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.13 | Benign | 0.00 | Affected | 0.1223 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2302G>T | D768Y 2D AIThe SynGAP1 missense variant D768Y is listed in ClinVar with status “Uncertain” (ClinVar ID 1061652.0) and is present in gnomAD (variant ID 6‑33442460‑G‑T). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic impact, which does not contradict the ClinVar designation of uncertainty. Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | Uncertain | 1 | 6-33442460-G-T | -9.866 | Likely Pathogenic | 0.824 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.86 | Deleterious | 0.989 | Probably Damaging | 0.806 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0581 | 0.7525 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||
| c.1226T>G | M409R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409R is not reported in ClinVar and is present in gnomAD (ID 6‑33438131‑T‑G). Functional prediction tools cluster into two groups: benign (REVEL, SIFT, FATHMM, Rosetta) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Three tools give uncertain results (FoldX, Foldetta, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | 6-33438131-T-G | -12.795 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 1.47 | Ambiguous | 0.4 | 0.44 | Likely Benign | 0.96 | Ambiguous | 1.30 | Destabilizing | 0.485 | Likely Benign | -4.39 | Deleterious | 0.877 | Possibly Damaging | 0.807 | Possibly Damaging | 4.15 | Benign | 0.27 | Tolerated | 3.38 | 28 | 0.1537 | 0.0957 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1879G>A | A627T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. Two tools, premPS and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta also predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that A627T is most likely pathogenic, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -8.613 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 2.27 | Destabilizing | 0.3 | 2.33 | Destabilizing | 2.30 | Destabilizing | 0.80 | Ambiguous | 0.505 | Likely Pathogenic | -3.95 | Deleterious | 0.994 | Probably Damaging | 0.807 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1069 | 0.5403 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1950T>A | N650K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.1950T>G | N650K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650K is not reported in ClinVar and is present in gnomAD (ID 6‑33441209‑T‑G). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and Foldetta, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and Rosetta) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, indicating the variant is most likely pathogenic, and this is consistent with the lack of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | 6-33441209-T-G | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1750A>T | I584F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I584F missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining pathogenic‑predicating tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as deleterious. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” while AlphaMissense‑Optimized and Foldetta yield uncertain results and are therefore not used as evidence. No other folding‑stability methods provide definitive support. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | -13.582 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 3.20 | Destabilizing | 0.2 | 0.28 | Likely Benign | 1.74 | Ambiguous | 0.66 | Ambiguous | 0.618 | Likely Pathogenic | -3.47 | Deleterious | 0.980 | Probably Damaging | 0.808 | Possibly Damaging | -1.26 | Pathogenic | 0.04 | Affected | 0.0641 | 0.2150 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2960A>G | D987G 2D AIThe SynGAP1 missense variant D987G (ClinVar ID 1061058.0) is listed as ClinVar status Uncertain and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and ESM1b, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further indicate that AlphaMissense‑Optimized is uncertain, while Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, aligning with the SGM‑Consensus but contradicting the ClinVar Uncertain designation. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment is in conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | Uncertain | 1 | -4.782 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.79 | Deleterious | 0.943 | Possibly Damaging | 0.808 | Possibly Damaging | 2.45 | Pathogenic | 0.07 | Tolerated | 4.32 | 2 | 0.3835 | 0.6710 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.3004C>T | H1002Y 2D AIThe SynGAP1 missense variant H1002Y is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign interpretation. Therefore, the variant is most likely benign based on the current predictive evidence, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -6.159 | Likely Benign | 0.489 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -1.85 | Neutral | 0.961 | Probably Damaging | 0.808 | Possibly Damaging | 2.74 | Benign | 0.14 | Tolerated | 0.1243 | 0.4427 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.657T>G | C219W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and premPS are inconclusive. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -16.565 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 10.10 | Destabilizing | 3.6 | 1.20 | Ambiguous | 5.65 | Destabilizing | 0.52 | Ambiguous | 0.706 | Likely Pathogenic | -9.23 | Deleterious | 0.997 | Probably Damaging | 0.808 | Possibly Damaging | 5.77 | Benign | 0.00 | Affected | 0.1131 | 0.3285 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.122G>C | R41P 2D  AIThe SynGAP1 missense variant R41P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R41P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.311707 | Structured | 0.431757 | Uncertain | 0.344 | 0.765 | 0.375 | -3.863 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.70 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.2244 | 0.5735 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.140G>C | R47P 2D AIThe SynGAP1 missense variant R47P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant and is likewise unavailable. High‑accuracy tools specifically indicate a benign prediction from AlphaMissense‑Optimized, while the other high‑accuracy methods (SGM Consensus, Foldetta) provide no definitive assessment. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | -10.316 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 0.195 | Likely Benign | -1.63 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.2050 | 0.4956 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.648G>C | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | 0.638 | Likely Pathogenic | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 0.1909 | 0.4660 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.648G>T | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | 0.638 | Likely Pathogenic | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 0.1909 | 0.4660 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.74G>C | R25P 2D AIThe SynGAP1 missense variant R25P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.394 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.155 | Likely Benign | -1.56 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.2217 | 0.4571 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.92G>C | R31P 2D AIThe SynGAP1 missense variant R31P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact for R31P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.185 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -1.64 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 0.2220 | 0.5005 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2441C>A | A814D 2D AIThe SynGAP1 missense variant A814D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result. Overall, the balance of evidence from the consensus of standard predictors points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.641 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.56 | Deleterious | 0.968 | Probably Damaging | 0.810 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1740 | 0.2167 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3056G>C | R1019P 2D AIThe SynGAP1 missense variant R1019P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of conventional tools predict a pathogenic effect, but the most accurate single‑tool prediction is benign and the consensus and folding‑stability analyses are inconclusive. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -3.737 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | -2.48 | Neutral | 0.966 | Probably Damaging | 0.811 | Possibly Damaging | 2.38 | Pathogenic | 0.01 | Affected | 0.1899 | 0.4521 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3979C>G | P1327A 2D AIThe SynGAP1 missense variant P1327A is reported in gnomAD (ID 6‑33451853‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-G | 2 | 1.28e-6 | -4.661 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.980 | Probably Damaging | 0.811 | Possibly Damaging | 4.24 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3152 | 0.3645 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.2650C>T | R884W 2D AIThe SynGAP1 missense variant R884W is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443202‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta (protein‑folding stability) result is available for this variant. Overall, the majority of computational predictions, including the high‑accuracy tools, indicate that R884W is most likely benign, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | Uncertain | 1 | 6-33443202-C-T | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.151 | Likely Benign | 0.26 | Neutral | 0.995 | Probably Damaging | 0.812 | Possibly Damaging | 2.56 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1223 | 0.3304 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2860C>T | P954S 2D AIThe SynGAP1 missense variant P954S is listed in ClinVar as Benign (ClinVar ID 833606.0) and is present in gnomAD (ID 6‑33443412‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | Likely Benign | 1 | 6-33443412-C-T | 1 | 6.20e-7 | -3.525 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.25 | Neutral | 0.954 | Possibly Damaging | 0.812 | Possibly Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3088 | 0.5619 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2861C>T | P954L 2D AIThe SynGAP1 missense variant P954L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.607 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.43 | Neutral | 0.977 | Probably Damaging | 0.812 | Possibly Damaging | 2.78 | Benign | 0.55 | Tolerated | 0.2346 | 0.5867 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>C | E1296A 2D AIThe SynGAP1 missense variant E1296A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are missing. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.562 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.238 | Likely Benign | -4.08 | Deleterious | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.61 | Benign | 0.02 | Affected | 0.3664 | 0.5506 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3888G>C | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.299 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3888G>T | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.493 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2644G>T | G882W 2D AIThe SynGAP1 missense variant G882W has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -8.637 | Likely Pathogenic | 0.606 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -2.35 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.01 | Pathogenic | 0.00 | Affected | 0.0829 | 0.4616 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>T | G973W 2D AIThe SynGAP1 missense variant G973W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G973W, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -6.896 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0846 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3175G>T | G1059W 2D AIThe SynGAP1 missense variant G1059W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -11.549 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.0925 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3956C>A | A1319D 2D AIThe SynGAP1 missense variant A1319D is reported in gnomAD (ID 6‑33451830‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319D, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-A | -5.156 | Likely Benign | 0.297 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.85 | Neutral | 0.971 | Probably Damaging | 0.813 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2290 | 0.2702 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.907G>T | G303W 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -9.041 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 1.69 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.40 | Ambiguous | 0.28 | Likely Benign | 0.157 | Likely Benign | -1.63 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.0663 | 0.4553 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.1191C>G | C397W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus, whereas pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, but Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Overall, the majority of tools lean toward a benign effect, and this is consistent with the lack of ClinVar evidence. Therefore, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -6.857 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 2.40 | Destabilizing | 2.3 | 4.46 | Destabilizing | 3.43 | Destabilizing | 0.19 | Likely Benign | 0.545 | Likely Pathogenic | -1.87 | Neutral | 0.987 | Probably Damaging | 0.814 | Possibly Damaging | 4.64 | Benign | 0.02 | Affected | 0.1637 | 0.5092 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.2692T>A | S898T 2D AIThe SynGAP1 missense variant S898T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.910 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.33 | Neutral | 0.992 | Probably Damaging | 0.814 | Possibly Damaging | 2.50 | Benign | 0.78 | Tolerated | 0.1833 | 0.6209 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2212A>T | S738C 2D AIThe SynGAP1 missense variant S738C is reported in ClinVar as not yet classified and is present in gnomAD (variant ID 6‑33441677‑A‑T). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. High‑accuracy methods give a benign result from AlphaMissense‑Optimized and a likely benign consensus from SGM‑Consensus; Foldetta predictions are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | 6-33441677-A-T | 4 | 2.48e-6 | -6.373 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.09 | Neutral | 0.975 | Probably Damaging | 0.815 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1112 | 0.3982 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.550G>C | E184Q 2D AIThe SynGAP1 missense variant E184Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -11.927 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.210 | Likely Benign | -2.55 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 0.1688 | 0.7914 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.577G>A | A193T 2D AIThe SynGAP1 missense variant A193T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.973 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.208 | Likely Benign | -1.36 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 4.07 | Benign | 0.21 | Tolerated | 0.1452 | 0.7231 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.730G>C | E244Q 2D AIThe SynGAP1 E244Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, six tools predict pathogenicity versus five predicting benignity, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.245 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.9 | -0.77 | Ambiguous | -0.27 | Likely Benign | 0.40 | Likely Benign | 0.695 | Likely Pathogenic | -2.49 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.78 | Benign | 0.05 | Affected | 0.1016 | 0.5610 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.731A>G | E244G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational evidence points to the variant being most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.452 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.28 | Ambiguous | 0.0 | 0.74 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | 0.900 | Likely Pathogenic | -5.67 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.73 | Benign | 0.01 | Affected | 0.2266 | 0.5252 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.745G>A | A249T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249T is listed in ClinVar (ID 1031675.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the balance of evidence favors a benign interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | Uncertain | 1 | -3.564 | Likely Benign | 0.805 | Likely Pathogenic | Ambiguous | 1.50 | Ambiguous | 0.6 | 1.39 | Ambiguous | 1.45 | Ambiguous | 0.30 | Likely Benign | 0.487 | Likely Benign | -0.96 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.65 | Benign | 0.40 | Tolerated | 3.39 | 15 | 0.0909 | 0.4972 | 1 | 0 | -2.5 | 30.03 | 214.5 | -43.3 | 0.0 | 0.0 | 0.5 | 0.2 | X | Potentially Benign | The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations. | ||||||||||||||||
| c.899C>G | S300C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437804‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | 6-33437804-C-G | -6.749 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.2 | 1.45 | Ambiguous | 0.88 | Ambiguous | 0.34 | Likely Benign | 0.129 | Likely Benign | -2.45 | Neutral | 0.975 | Probably Damaging | 0.815 | Possibly Damaging | 1.55 | Pathogenic | 0.01 | Affected | 3.47 | 19 | 0.1005 | 0.6493 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.299A>G | Y100C 2D  AIThe SynGAP1 missense variant Y100C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | -3.789 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.88 | Neutral | 0.994 | Probably Damaging | 0.816 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.3073 | 0.2213 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.2810A>G | D937G 2D AIThe SynGAP1 missense variant D937G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that D937G is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -0.770 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.817 | Possibly Damaging | 2.82 | Benign | 0.72 | Tolerated | 0.4313 | 0.7006 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1825G>A | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | 0.520 | Likely Pathogenic | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | 0.1158 | 0.4348 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1825G>C | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | 0.520 | Likely Pathogenic | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | 0.1158 | 0.4348 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1826G>T | G609V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS and AlphaMissense‑Optimized, whereas the remaining 10 tools (SGM Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) all predict pathogenicity. High‑accuracy assessments further highlight the discordance: AlphaMissense‑Optimized reports a benign effect, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate pathogenicity. With the majority of evidence pointing to deleterious impact, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -11.049 | Likely Pathogenic | 0.374 | Ambiguous | Likely Benign | 4.17 | Destabilizing | 0.3 | 3.77 | Destabilizing | 3.97 | Destabilizing | 0.34 | Likely Benign | 0.734 | Likely Pathogenic | -4.47 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.48 | Pathogenic | 0.02 | Affected | 0.1269 | 0.3317 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2353C>G | R785G 2D AIThe SynGAP1 missense variant R785G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments further reveal that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus again suggests pathogenicity; Foldetta stability analysis is not available for this variant. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the SGM‑Consensus result. Because the variant is not present in ClinVar, there is no existing clinical classification to contradict; thus, based on the available computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -3.684 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -3.44 | Deleterious | 0.980 | Probably Damaging | 0.818 | Possibly Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.3695 | 0.3686 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2560C>G | R854G 2D AIThe SynGAP1 missense variant R854G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign score, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.346 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -1.92 | Neutral | 0.980 | Probably Damaging | 0.818 | Possibly Damaging | 4.08 | Benign | 0.03 | Affected | 0.3469 | 0.3764 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3449C>G | A1150G 2D AIThe SynGAP1 A1150G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.089 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -2.37 | Neutral | 0.983 | Probably Damaging | 0.818 | Possibly Damaging | 2.32 | Pathogenic | 0.09 | Tolerated | 0.2263 | 0.4741 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1280A>C | H427P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools are uncertain: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for H427P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -11.098 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 4.74 | Destabilizing | 0.1 | 7.61 | Destabilizing | 6.18 | Destabilizing | 0.68 | Ambiguous | 0.324 | Likely Benign | -4.22 | Deleterious | 0.993 | Probably Damaging | 0.819 | Possibly Damaging | 3.51 | Benign | 0.01 | Affected | 0.2061 | 0.3442 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1983G>C | Q661H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q661H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain calls are made by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments indicate that the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts a pathogenic effect, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign outcome. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not conflict with ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -9.938 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.78 | Ambiguous | 0.1 | 0.07 | Likely Benign | 0.43 | Likely Benign | 0.09 | Likely Benign | 0.282 | Likely Benign | -3.78 | Deleterious | 0.993 | Probably Damaging | 0.819 | Possibly Damaging | 3.42 | Benign | 0.02 | Affected | 0.1276 | 0.3424 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1983G>T | Q661H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q661H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain calls are made by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments indicate that the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts a pathogenic effect, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign outcome. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not conflict with ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -9.938 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.78 | Ambiguous | 0.1 | 0.07 | Likely Benign | 0.43 | Likely Benign | 0.09 | Likely Benign | 0.282 | Likely Benign | -3.78 | Deleterious | 0.993 | Probably Damaging | 0.819 | Possibly Damaging | 3.42 | Benign | 0.02 | Affected | 0.1276 | 0.3424 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.2404G>T | G802C 2D AIThe SynGAP1 missense variant G802C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification for G802C. This conclusion is consistent with the lack of any ClinVar pathogenic annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -6.332 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -1.60 | Neutral | 0.983 | Probably Damaging | 0.819 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.1426 | 0.4126 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.2978C>A | P993H 2D AIThe SynGAP1 missense variant P993H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P993H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.535 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.93 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.1799 | 0.4591 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3404A>T | K1135M 2D AIThe SynGAP1 K1135M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | -5.953 | Likely Benign | 0.931 | Likely Pathogenic | Ambiguous | 0.423 | Likely Benign | -1.65 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.1669 | 0.4164 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3536A>C | K1179T 2D AIThe SynGAP1 missense variant K1179T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are not available. Taken together, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.637480 | Disordered | 0.558455 | Binding | 0.575 | 0.678 | 0.250 | -4.447 | Likely Benign | 0.927 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.80 | Neutral | 0.975 | Probably Damaging | 0.819 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.2107 | 0.2027 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.3586A>C | K1196Q 2D AIThe SynGAP1 missense variant K1196Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -5.222 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.342 | Likely Benign | -0.65 | Neutral | 0.989 | Probably Damaging | 0.819 | Possibly Damaging | 5.38 | Benign | 0.07 | Tolerated | 0.3814 | 0.0945 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3588G>C | K1196N 2D AIThe SynGAP1 missense variant K1196N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenicity, whereas the SGM‑Consensus indicates benignity; a Foldetta stability analysis is unavailable. Overall, the majority of tools (five pathogenic vs. four benign) suggest the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -6.421 | Likely Benign | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.305 | Likely Benign | -1.73 | Neutral | 0.994 | Probably Damaging | 0.819 | Possibly Damaging | 5.37 | Benign | 0.04 | Affected | 0.3251 | 0.1145 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3588G>T | K1196N 2D AIThe SynGAP1 missense variant K1196N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments further divide the evidence: AlphaMissense‑Optimized predicts a pathogenic effect, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. With no ClinVar classification to resolve the conflict, the overall computational signal is inconclusive, but the presence of a pathogenic prediction from a high‑accuracy model and the absence of a benign consensus suggest the variant is more likely pathogenic. This assessment does not contradict any ClinVar status, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -6.421 | Likely Benign | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.305 | Likely Benign | -1.73 | Neutral | 0.994 | Probably Damaging | 0.819 | Possibly Damaging | 5.37 | Benign | 0.04 | Affected | 0.3251 | 0.1145 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.557T>G | L186W 2D  AIThe SynGAP1 missense variant L186W has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -16.177 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -4.78 | Deleterious | 0.996 | Probably Damaging | 0.819 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0539 | 0.3138 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.1297G>C | A433P 2D 3DClick to see structure in 3D Viewer AISynGAP1 A433P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, SIFT, and FATHMM. Those that predict pathogenicity comprise FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. The remaining tools, premPS and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Therefore, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -9.887 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 2.48 | Destabilizing | 0.0 | 7.09 | Destabilizing | 4.79 | Destabilizing | 0.55 | Ambiguous | 0.217 | Likely Benign | -2.64 | Deleterious | 0.998 | Probably Damaging | 0.820 | Possibly Damaging | 3.37 | Benign | 0.07 | Tolerated | 0.1471 | 0.4150 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1586T>C | I529T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification—there is no contradiction between the predictions and the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | Uncertain | 1 | -0.539 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.16 | Likely Benign | 0.19 | Likely Benign | 0.17 | Likely Benign | 0.343 | Likely Benign | 0.24 | Neutral | 0.872 | Possibly Damaging | 0.820 | Possibly Damaging | -1.23 | Pathogenic | 0.55 | Tolerated | 3.37 | 35 | 0.0897 | 0.0989 | 0 | -1 | -5.2 | -12.05 | 207.2 | 29.8 | 0.2 | 0.0 | 0.2 | 0.1 | X | Potentially Benign | Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.1586T>G | I529S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign classification and is consistent with the absence of a ClinVar assertion. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | -0.171 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.3 | -0.53 | Ambiguous | -0.20 | Likely Benign | 0.00 | Likely Benign | 0.383 | Likely Benign | 1.62 | Neutral | 0.979 | Probably Damaging | 0.820 | Possibly Damaging | -1.14 | Pathogenic | 0.40 | Tolerated | 0.2402 | 0.0887 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2902G>T | G968C 2D AIThe SynGAP1 missense variant G968C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -8.441 | Likely Pathogenic | 0.117 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -0.99 | Neutral | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 4.12 | Benign | 0.07 | Tolerated | 0.1294 | 0.4768 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3322A>T | S1108C 2D AIThe SynGAP1 missense variant S1108C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification, and this conclusion does not contradict any ClinVar status because none is available. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -9.189 | Likely Pathogenic | 0.183 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -3.30 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0.0992 | 0.5299 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3875T>A | L1292H 2D AIThe SynGAP1 missense variant L1292H is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33447923‑T‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with a slight tilt toward pathogenicity (five pathogenic vs. four benign). Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | 6-33447923-T-A | -5.692 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -4.42 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1271 | 0.0649 | -3 | -2 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||
| c.2813G>C | G938A 2D AIThe SynGAP1 missense variant G938A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta’s protein‑folding stability analysis is not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.068 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.41 | Neutral | 0.979 | Probably Damaging | 0.821 | Possibly Damaging | 2.80 | Benign | 0.82 | Tolerated | 0.3462 | 0.4948 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2110A>C | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in gnomAD and has no ClinVar entry. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain stability results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.178 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2112C>A | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus confirms Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no additional evidence. Overall, the preponderance of evidence from multiple independent predictors indicates that S704R is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.200 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2112C>G | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). FoldX and Rosetta give uncertain results, and Foldetta (a combined FoldX‑MD/Rosetta stability assessment) is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.200 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.3275T>C | L1092S 2D AIThe SynGAP1 missense variant L1092S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -3.649 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.121 | Likely Benign | -0.42 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.68 | Benign | 0.25 | Tolerated | 0.3086 | 0.1119 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3276G>C | L1092F 2D AIThe SynGAP1 missense variant L1092F is reported in gnomAD (6‑33443828‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | 6-33443828-G-C | 1 | 6.40e-7 | -5.010 | Likely Benign | 0.623 | Likely Pathogenic | Likely Benign | 0.067 | Likely Benign | -1.40 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.63 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.0772 | 0.4060 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||
| c.3276G>T | L1092F 2D AIThe SynGAP1 missense variant L1092F is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -5.010 | Likely Benign | 0.623 | Likely Pathogenic | Likely Benign | 0.067 | Likely Benign | -1.40 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.63 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.0772 | 0.4060 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.1015A>C | K339Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evaluated tools (8 pathogenic vs. 4 benign) indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -10.952 | Likely Pathogenic | 0.863 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.0 | -0.50 | Ambiguous | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.458 | Likely Benign | -3.06 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 1.90 | Pathogenic | 0.04 | Affected | 0.4041 | 0.1012 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.104T>G | V35G 2D AIThe SynGAP1 missense variant V35G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus also predicts benign; Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | -3.614 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.143 | Likely Benign | 0.66 | Neutral | 0.693 | Possibly Damaging | 0.824 | Possibly Damaging | 4.41 | Benign | 0.00 | Affected | 0.1514 | 0.2618 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1298C>A | A433E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools (premPS and AlphaMissense‑Default) give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports benign. No prediction is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -8.210 | Likely Pathogenic | 0.506 | Ambiguous | Likely Benign | -0.20 | Likely Benign | 0.0 | 0.15 | Likely Benign | -0.03 | Likely Benign | 0.58 | Ambiguous | 0.148 | Likely Benign | -1.65 | Neutral | 0.998 | Probably Damaging | 0.824 | Possibly Damaging | 3.42 | Benign | 0.18 | Tolerated | 0.0783 | 0.1695 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||
| c.1388A>G | D463G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools favor pathogenicity versus three favor benign, with the remaining five (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yielding uncertain results. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -10.713 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.66 | Ambiguous | 0.1 | 1.93 | Ambiguous | 1.30 | Ambiguous | 0.54 | Ambiguous | 0.422 | Likely Benign | -6.36 | Deleterious | 0.994 | Probably Damaging | 0.824 | Possibly Damaging | 3.32 | Benign | 0.09 | Tolerated | 0.3751 | 0.4898 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2014A>C | T672P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T672P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact for T672P. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | -11.022 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 2.22 | Destabilizing | 0.2 | 5.54 | Destabilizing | 3.88 | Destabilizing | 0.55 | Ambiguous | 0.087 | Likely Benign | -4.20 | Deleterious | 0.968 | Probably Damaging | 0.824 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.1988 | 0.5532 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.2431C>T | P811S 2D AIThe SynGAP1 missense variant P811S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not contribute to the evidence. Overall, the preponderance of evidence points to a benign effect for P811S, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -4.733 | Likely Benign | 0.474 | Ambiguous | Likely Benign | 0.128 | Likely Benign | -1.28 | Neutral | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.79 | Benign | 0.78 | Tolerated | 0.3656 | 0.5960 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>T | P811L 2D AIThe SynGAP1 P811L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from high‑accuracy tools and consensus methods indicates that P811L is most likely benign. This assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -6.184 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -3.98 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.71 | Benign | 0.01 | Affected | 0.2327 | 0.6621 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2435C>T | P812L 2D AIThe SynGAP1 P812L missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33442987‑C‑T). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, which is consistent with the lack of ClinVar reporting but does not contradict it. Thus, based on the available computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | 6-33442987-C-T | 1 | 6.20e-7 | -7.121 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -2.61 | Deleterious | 0.978 | Probably Damaging | 0.824 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 4.32 | 4 | 0.2131 | 0.6634 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2452C>T | P818S 2D AIThe SynGAP1 missense variant P818S is catalogued in gnomAD (ID 6‑33443004‑C‑T) but has no ClinVar entry. Functional prediction tools split in two groups: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments are limited: AlphaMissense‑Optimized yields an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this residue. Taken together, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status because none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | 6-33443004-C-T | 1 | 6.20e-7 | -5.740 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.203 | Likely Benign | -4.38 | Deleterious | 0.989 | Probably Damaging | 0.824 | Possibly Damaging | 2.04 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3581 | 0.6199 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.257T>G | V86G 2D AIThe SynGAP1 missense variant V86G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which evaluates protein‑folding stability via FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence (five pathogenic versus four benign predictions) indicates that V86G is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.685117 | Disordered | 0.552911 | Binding | 0.295 | 0.887 | 0.500 | -4.212 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.130 | Likely Benign | -2.50 | Deleterious | 0.307 | Benign | 0.824 | Possibly Damaging | 3.74 | Benign | 0.00 | Affected | 0.2321 | 0.2547 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.956C>T | A319V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also inconclusive. Overall, the majority of evidence points to a benign effect, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -8.179 | Likely Pathogenic | 0.141 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.4 | 0.63 | Ambiguous | 0.61 | Ambiguous | 0.23 | Likely Benign | 0.329 | Likely Benign | -2.32 | Neutral | 0.989 | Probably Damaging | 0.824 | Possibly Damaging | 1.88 | Pathogenic | 0.10 | Tolerated | 0.1094 | 0.6390 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.2206C>T | R736C 2D AISynGAP1 missense variant R736C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441671‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign effect, which does not conflict with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | Conflicting | 3 | 6-33441671-C-T | 8 | 4.96e-6 | -7.113 | In-Between | 0.120 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -2.06 | Neutral | 0.999 | Probably Damaging | 0.825 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 4.07 | 3 | 0.3740 | 0.1691 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.2635G>C | A879P 2D AIThe SynGAP1 missense variant A879P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A879P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -4.317 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -1.16 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1713 | 0.5004 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3082C>A | L1028M 2D AIThe SynGAP1 missense variant L1028M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -4.591 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.07 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.70 | Benign | 0.18 | Tolerated | 0.0776 | 0.3124 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>A | L1028Q 2D AIThe SynGAP1 missense variant L1028Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.718 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -0.19 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.80 | Benign | 0.38 | Tolerated | 0.1110 | 0.1403 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3311C>A | P1104Q 2D AIThe SynGAP1 missense variant P1104Q is reported in gnomAD (ID 6‑33443863‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | 6-33443863-C-A | -3.161 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.64 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1498 | 0.5063 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3511_3512delinsTG | A1171C 2D  AIThe SynGAP1 missense variant A1171C (ClinVar ID 1723483.0) is listed as “Uncertain” in ClinVar and is not present in gnomAD. Prediction tools that converge on a benign outcome include PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which report a benign or neutral effect. In contrast, PolyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign,” reinforcing the benign signal. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | Uncertain | 1 | -5.363 | Likely Benign | 0.496 | Ambiguous | Likely Benign | -1.16 | Neutral | 0.978 | Probably Damaging | 0.825 | Possibly Damaging | 5.32 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1102 | 0.4921 | -2 | 0 | 0.7 | 32.06 | ||||||||||||||||||||||||||||||||||||
| c.3788T>G | I1263S 2D AIThe SynGAP1 missense variant I1263S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -8.074 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | -4.97 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.3242 | 0.0910 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3827A>T | D1276V 2D AIThe SynGAP1 D1276V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.725 | Likely Benign | 0.851 | Likely Pathogenic | Ambiguous | 0.331 | Likely Benign | -6.66 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.19 | Pathogenic | 0.00 | Affected | 0.0614 | 0.5207 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>C | N1306H 2D AIThe SynGAP1 missense variant N1306H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is labeled “Likely Benign”). In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -2.949 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -3.42 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.1705 | 0.7846 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>T | N1306Y 2D AIThe SynGAP1 missense variant N1306Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -4.193 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.273 | Likely Benign | -5.59 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.0732 | 0.6658 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.818A>T | E273V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and premPS. The majority of tools predict a pathogenic impact: Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, SGM‑Consensus (Likely Pathogenic), and Foldetta. Two tools give inconclusive results: AlphaMissense‑Optimized (Uncertain) and FoldX (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. Overall, the consensus of pathogenic‑predicting tools outweighs the benign predictions, indicating that E273V is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | -11.671 | Likely Pathogenic | 0.814 | Likely Pathogenic | Ambiguous | 1.93 | Ambiguous | 0.3 | 3.31 | Destabilizing | 2.62 | Destabilizing | 0.17 | Likely Benign | 0.361 | Likely Benign | -4.66 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.70 | Pathogenic | 0.01 | Affected | 0.0811 | 0.3813 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.985C>T | R329C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R329C is reported in gnomAD (ID 6‑33437890‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools remain inconclusive: premPS and AlphaMissense‑Optimized. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Overall, six tools favor pathogenicity versus five favor benign, with one uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | 6-33437890-C-T | 2 | 1.24e-6 | -9.433 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.42 | Likely Benign | 0.69 | Ambiguous | 0.313 | Likely Benign | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.825 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 3.41 | 15 | 0.3553 | 0.2921 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||||
| c.2861C>G | P954R 2D AIThe SynGAP1 missense variant P954R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that P954R is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -6.329 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.19 | Neutral | 0.954 | Possibly Damaging | 0.826 | Possibly Damaging | 2.78 | Benign | 0.11 | Tolerated | 0.1548 | 0.3940 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2336G>T | S779I 2D AIThe SynGAP1 missense variant S779I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy methods give a benign call from AlphaMissense‑Optimized; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) suggest a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -6.261 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.198 | Likely Benign | -2.10 | Neutral | 0.918 | Possibly Damaging | 0.827 | Possibly Damaging | 2.28 | Pathogenic | 0.05 | Affected | 0.1046 | 0.6248 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2531T>A | L844Q 2D AIThe SynGAP1 missense variant L844Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | -3.989 | Likely Benign | 0.856 | Likely Pathogenic | Ambiguous | 0.172 | Likely Benign | -2.17 | Neutral | 0.960 | Probably Damaging | 0.827 | Possibly Damaging | 2.60 | Benign | 0.01 | Affected | 0.1146 | 0.1105 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3425C>T | S1142F 2D AIThe SynGAP1 missense variant S1142F has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority, and Foldetta data are unavailable. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -5.074 | Likely Benign | 0.508 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -3.70 | Deleterious | 0.918 | Possibly Damaging | 0.827 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.0861 | 0.5603 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.100T>A | Y34N 2D AIThe SynGAP1 missense variant Y34N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -3.153 | Likely Benign | 0.214 | Likely Benign | Likely Benign | 0.165 | Likely Benign | -1.01 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 4.16 | Benign | 0.00 | Affected | 0.2410 | 0.1322 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.100T>G | Y34D 2D AIThe SynGAP1 missense variant Y34D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -2.653 | Likely Benign | 0.357 | Ambiguous | Likely Benign | 0.199 | Likely Benign | -1.20 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.4092 | 0.1322 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.104T>A | V35D 2D AIThe SynGAP1 missense variant V35D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Overall, the majority of evidence points to the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | -4.232 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -0.42 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.1540 | 0.1547 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.110C>T | S37F 2D AIThe SynGAP1 missense variant S37F is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). AlphaMissense‑Default is uncertain, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -4.258 | Likely Benign | 0.412 | Ambiguous | Likely Benign | 0.131 | Likely Benign | -1.77 | Neutral | 0.676 | Possibly Damaging | 0.828 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1060 | 0.5552 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.115T>A | Y39N 2D AIThe SynGAP1 missense variant Y39N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.098 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.84 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 0.2375 | 0.0903 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.115T>G | Y39D 2D AIThe SynGAP1 missense variant Y39D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Y39D, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -2.338 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -1.86 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.4099 | 0.0903 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2600G>C | G867A 2D AIThe SynGAP1 missense variant G867A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -4.638 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.18 | Neutral | 0.990 | Probably Damaging | 0.828 | Possibly Damaging | 2.79 | Benign | 0.94 | Tolerated | 0.3666 | 0.5534 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2765G>T | R922L 2D AIThe SynGAP1 missense variant R922L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign interpretation. Therefore, the variant is most likely benign according to the consensus of predictive tools, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -3.714 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 0.150 | Likely Benign | 0.84 | Neutral | 0.983 | Probably Damaging | 0.828 | Possibly Damaging | 3.04 | Benign | 1.00 | Tolerated | 0.2033 | 0.5022 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2900G>C | R967P 2D AIThe SynGAP1 missense variant R967P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for R967P, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.974374 | Disordered | 0.969686 | Binding | 0.340 | 0.888 | 0.750 | -2.506 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -0.76 | Neutral | 0.996 | Probably Damaging | 0.828 | Possibly Damaging | 4.14 | Benign | 0.17 | Tolerated | 0.2145 | 0.5533 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3640C>G | R1214G 2D AIThe SynGAP1 missense variant R1214G is listed in gnomAD (6‑33446632‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized; those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the majority of tools predict a pathogenic impact, and this conclusion is not contradicted by any ClinVar status (none). Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | 6-33446632-C-G | 1 | 6.20e-7 | -9.697 | Likely Pathogenic | 0.725 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -4.41 | Deleterious | 0.992 | Probably Damaging | 0.828 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3229 | 0.2361 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||
| c.3641G>T | R1214L 2D AIThe SynGAP1 missense variant R1214L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments are limited: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta data are unavailable. Overall, the majority of available predictions (four pathogenic versus three benign) suggest a pathogenic impact. This conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | -7.058 | In-Between | 0.510 | Ambiguous | Likely Benign | 0.114 | Likely Benign | -3.65 | Deleterious | 0.992 | Probably Damaging | 0.828 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1497 | 0.2988 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3745A>G | R1249G 2D AIThe SynGAP1 missense variant R1249G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; ESM1b is uncertain and SGM‑Consensus is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.745909 | Disordered | 0.366265 | Uncertain | 0.874 | 0.556 | 0.875 | -7.405 | In-Between | 0.684 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | -5.38 | Deleterious | 0.990 | Probably Damaging | 0.828 | Possibly Damaging | 1.70 | Pathogenic | 0.00 | Affected | 0.3087 | 0.2393 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3747G>C | R1249S 2D AIThe SynGAP1 missense variant R1249S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and labels the variant as Likely Pathogenic. High‑accuracy assessments are limited: AlphaMissense‑Optimized returns an Uncertain result, and the Foldetta stability analysis is not available for this residue. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because no ClinVar entry exists for R1249S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.745909 | Disordered | 0.366265 | Uncertain | 0.874 | 0.556 | 0.875 | -6.936 | Likely Benign | 0.828 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -4.52 | Deleterious | 0.980 | Probably Damaging | 0.828 | Possibly Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.2777 | 0.1843 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3747G>T | R1249S 2D AIThe SynGAP1 missense variant R1249S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and labels the variant as Likely Pathogenic. High‑accuracy assessments are limited: AlphaMissense‑Optimized returns an Uncertain result, and the Foldetta stability analysis is not available for this residue. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because no ClinVar entry exists for R1249S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.745909 | Disordered | 0.366265 | Uncertain | 0.874 | 0.556 | 0.875 | -6.936 | Likely Benign | 0.828 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -4.52 | Deleterious | 0.980 | Probably Damaging | 0.828 | Possibly Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.2777 | 0.1843 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.602A>C | D201A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201A variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic, and Foldetta remains inconclusive. Overall, the majority of standard tools favor a benign classification, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s impact uncertain. The predictions do not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.793 | In-Between | 0.769 | Likely Pathogenic | Likely Benign | 0.45 | Likely Benign | 0.1 | 1.86 | Ambiguous | 1.16 | Ambiguous | 0.23 | Likely Benign | 0.261 | Likely Benign | -3.81 | Deleterious | 0.989 | Probably Damaging | 0.828 | Possibly Damaging | 4.11 | Benign | 0.09 | Tolerated | 0.3177 | 0.5050 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||
| c.2708G>C | G903A 2D AIThe SynGAP1 missense variant G903A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G903A. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -2.843 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.54 | Neutral | 0.989 | Probably Damaging | 0.829 | Possibly Damaging | 2.43 | Pathogenic | 0.08 | Tolerated | 0.3490 | 0.5025 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.307G>T | G103C 2D AIThe SynGAP1 missense variant G103C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for G103C, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -5.681 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -1.12 | Neutral | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.1494 | 0.3767 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3619G>A | E1207K 2D AIThe SynGAP1 missense variant E1207K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E1207K. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -8.145 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 0.261 | Likely Benign | -2.88 | Deleterious | 0.978 | Probably Damaging | 0.829 | Possibly Damaging | 2.12 | Pathogenic | 0.02 | Affected | 0.1796 | 0.4234 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3620A>C | E1207A 2D AIThe SynGAP1 missense variant E1207A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized indicates a benign effect, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a pathogenic effect for E1207A, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -8.277 | Likely Pathogenic | 0.679 | Likely Pathogenic | Likely Benign | 0.295 | Likely Benign | -4.27 | Deleterious | 0.989 | Probably Damaging | 0.829 | Possibly Damaging | 2.11 | Pathogenic | 0.02 | Affected | 0.3019 | 0.4305 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.605A>G | E202G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic (2 pathogenic, 1 benign, 1 uncertain). Foldetta remains uncertain. Overall, the majority of standard prediction tools suggest a benign effect, and this conclusion does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -8.310 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.56 | Ambiguous | 0.27 | Likely Benign | 0.259 | Likely Benign | -4.70 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 0.3061 | 0.5405 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.619A>C | K207Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K207Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; AlphaMissense‑Optimized is uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Folding‑stability scores from FoldX and Rosetta are inconclusive, and premPS is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -9.544 | Likely Pathogenic | 0.874 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.00 | Likely Benign | 0.61 | Ambiguous | 0.250 | Likely Benign | -2.95 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.00 | Benign | 0.10 | Tolerated | 0.4010 | 0.1797 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.621G>C | K207N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence points to a pathogenic effect for K207N, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.123 | Likely Benign | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 0.3184 | 0.2335 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.621G>T | K207N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K207N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus (majority vote) also predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that K207N is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.124 | Likely Benign | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 0.3184 | 0.2335 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.626T>A | V209E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all predict a pathogenic outcome. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, V209E is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -14.366 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 1.3 | 2.35 | Destabilizing | 2.94 | Destabilizing | 1.52 | Destabilizing | 0.403 | Likely Benign | -4.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.65 | Benign | 0.00 | Affected | 0.0826 | 0.1652 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.631A>C | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a pathogenic signal is reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools predict a pathogenic effect, and the high‑accuracy predictions reinforce this conclusion. The variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.132 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.633C>A | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, FATHMM, and Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions and the two high‑accuracy pathogenic calls suggest that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.144 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.633C>G | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, FATHMM, and the protein‑stability integrator Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and premPS is uncertain. High‑accuracy assessments give conflicting signals: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, but Foldetta, which combines FoldX‑MD and Rosetta outputs, predicts Benign. Overall, the majority of tools and the consensus score point to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.144 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.637A>T | I213F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213F missense variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; FoldX and premPS are uncertain and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain and thus not considered. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.212 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.7 | 2.66 | Destabilizing | 1.81 | Ambiguous | 0.73 | Ambiguous | 0.815 | Likely Pathogenic | -3.30 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.79 | Benign | 0.01 | Affected | 0.0473 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.638T>G | I213S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.858 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 1.1 | 2.95 | Destabilizing | 2.48 | Destabilizing | 1.53 | Destabilizing | 0.879 | Likely Pathogenic | -4.88 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | 0.2290 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.723A>C | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | 0.663 | Likely Pathogenic | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 0.3426 | 0.1872 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.723A>T | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | 0.663 | Likely Pathogenic | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 0.3426 | 0.1872 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.3519C>G | I1173M 2D AIThe SynGAP1 missense variant I1173M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -3.301 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.327 | Likely Benign | -0.61 | Neutral | 0.973 | Probably Damaging | 0.830 | Possibly Damaging | 5.37 | Benign | 0.15 | Tolerated | 0.0676 | 0.2295 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.1103C>T | P368L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P368L is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438008‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Based on the overall distribution of predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.363090 | Structured | 0.439989 | Uncertain | 0.580 | 0.677 | 0.250 | 6-33438008-C-T | 1 | 6.33e-7 | -6.520 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 1.52 | Ambiguous | 0.7 | 1.15 | Ambiguous | 1.34 | Ambiguous | 0.52 | Ambiguous | 0.248 | Likely Benign | -6.61 | Deleterious | 0.991 | Probably Damaging | 0.831 | Possibly Damaging | 1.77 | Pathogenic | 0.00 | Affected | 3.42 | 19 | 0.2336 | 0.7125 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.1178G>A | G393D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393D is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SIFT, ESM1b, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default all indicate pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized reports a benign outcome, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect for G393D, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -5.247 | Likely Benign | 0.717 | Likely Pathogenic | Likely Benign | 3.30 | Destabilizing | 1.4 | -1.00 | Ambiguous | 1.15 | Ambiguous | 0.57 | Ambiguous | 0.528 | Likely Pathogenic | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.831 | Possibly Damaging | 1.32 | Pathogenic | 0.19 | Tolerated | 0.2077 | 0.1645 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.227C>A | S76Y 2D AIThe SynGAP1 missense variant S76Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for S76Y, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | -4.243 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -2.35 | Neutral | 0.972 | Probably Damaging | 0.831 | Possibly Damaging | 3.71 | Benign | 0.00 | Affected | 0.0540 | 0.4753 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.227C>T | S76F 2D AIThe SynGAP1 missense variant S76F is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33425835-C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | 6-33425835-C-T | 4 | 2.48e-6 | -4.557 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -2.40 | Neutral | 0.972 | Probably Damaging | 0.831 | Possibly Damaging | 3.71 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0501 | 0.4887 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||
| c.1007A>T | K336M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS) and pathogenic predictions (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” Stability‑based assessments are inconclusive: Foldetta is uncertain, and Rosetta is also uncertain. High‑accuracy tools specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms pathogenic, while Foldetta remains uncertain. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -15.395 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.58 | Ambiguous | -0.23 | Likely Benign | 0.301 | Likely Benign | -5.07 | Deleterious | 0.989 | Probably Damaging | 0.832 | Possibly Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.1185 | 0.4760 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1012G>T | D338Y 2D AIThe SynGAP1 D338Y missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a deleterious effect: premPS is the sole predictor labeling it benign, whereas the remaining seven tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—classify it as pathogenic. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is also uncertain. Overall, the preponderance of evidence indicates that D338Y is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -14.190 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 1.10 | Ambiguous | 1.3 | 0.91 | Ambiguous | 1.01 | Ambiguous | 0.22 | Likely Benign | 0.552 | Likely Pathogenic | -6.49 | Deleterious | 0.989 | Probably Damaging | 0.832 | Possibly Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.0687 | 0.5609 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1591T>G | C531G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and AlphaMissense‑Optimized, while the majority of other in silico predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. Uncertain results come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -10.037 | Likely Pathogenic | 0.577 | Likely Pathogenic | Likely Benign | 0.47 | Likely Benign | 0.3 | 1.49 | Ambiguous | 0.98 | Ambiguous | 1.42 | Destabilizing | 0.545 | Likely Pathogenic | -9.76 | Deleterious | 0.985 | Probably Damaging | 0.832 | Possibly Damaging | -1.24 | Pathogenic | 0.00 | Affected | 0.2653 | 0.2297 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.2716C>G | L906V 2D AIThe SynGAP1 missense variant L906V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a damaging or pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a Likely Benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -5.105 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.64 | Neutral | 0.981 | Probably Damaging | 0.832 | Possibly Damaging | 2.46 | Pathogenic | 0.21 | Tolerated | 0.1632 | 0.3744 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.289G>C | E97Q 2D AIThe SynGAP1 missense variant E97Q is reported in gnomAD (ID 6‑33425897‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both consensus and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.609018 | Binding | 0.340 | 0.867 | 0.625 | 6-33425897-G-C | 2 | 1.24e-6 | -3.917 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.32 | Neutral | 0.978 | Probably Damaging | 0.832 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1507 | 0.7874 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.3667C>G | L1223V 2D AIThe SynGAP1 missense variant L1223V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic, reflecting a majority of pathogenic calls. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.608892 | Disordered | 0.436267 | Uncertain | 0.868 | 0.540 | 0.375 | -8.492 | Likely Pathogenic | 0.678 | Likely Pathogenic | Likely Benign | 0.178 | Likely Benign | -2.18 | Neutral | 0.981 | Probably Damaging | 0.832 | Possibly Damaging | 1.54 | Pathogenic | 0.04 | Affected | 0.1381 | 0.2988 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.620A>T | K207M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact; premPS is uncertain. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.596 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.22 | Likely Benign | 0.0 | -0.47 | Likely Benign | -0.35 | Likely Benign | 0.59 | Ambiguous | 0.336 | Likely Benign | -4.67 | Deleterious | 0.985 | Probably Damaging | 0.832 | Possibly Damaging | 3.94 | Benign | 0.03 | Affected | 0.0982 | 0.4705 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.709G>C | A237P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, Foldetta is pathogenic, and AlphaMissense‑Optimized is uncertain (treated as unavailable). Overall, the preponderance of evidence indicates that A237P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -9.119 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.5 | 4.20 | Destabilizing | 2.15 | Destabilizing | 1.04 | Destabilizing | 0.752 | Likely Pathogenic | -3.68 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.77 | Benign | 0.03 | Affected | 0.1593 | 0.3724 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.734A>T | N245I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, while those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -14.527 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | -0.56 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.26 | Likely Benign | 0.60 | Ambiguous | 0.831 | Likely Pathogenic | -7.46 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.88 | Benign | 0.00 | Affected | 0.0672 | 0.6999 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1292T>G | L431R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -14.777 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.45 | Destabilizing | 0.0 | 4.76 | Destabilizing | 4.11 | Destabilizing | 1.93 | Destabilizing | 0.654 | Likely Pathogenic | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.833 | Possibly Damaging | 2.93 | Benign | 0.00 | Affected | 0.1191 | 0.0730 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2527A>C | M843L 2D AIThe SynGAP1 missense variant M843L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -4.406 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -1.02 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.92 | Benign | 0.33 | Tolerated | 0.1717 | 0.4571 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2527A>T | M843L 2D AIThe SynGAP1 missense variant M843L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -4.406 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -1.02 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.92 | Benign | 0.33 | Tolerated | 0.1717 | 0.4571 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3238G>C | A1080P 2D AIThe SynGAP1 missense variant A1080P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A1080P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -2.429 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.15 | Neutral | 0.996 | Probably Damaging | 0.833 | Possibly Damaging | 3.96 | Benign | 0.02 | Affected | 0.1884 | 0.5324 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3481A>C | M1161L 2D AIThe SynGAP1 missense variant M1161L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Consequently, the available computational evidence is conflicting, with an equal number of benign and pathogenic predictions and no definitive high‑accuracy support. The variant is most likely of uncertain significance; this lack of consensus is consistent with its absence from ClinVar and gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.129 | Likely Benign | 0.862 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.59 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.38 | Pathogenic | 0.48 | Tolerated | 0.1614 | 0.4244 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3481A>T | M1161L 2D AISynGAP1 missense variant M1161L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall computational evidence does not strongly favor either outcome. The variant is most likely inconclusive in pathogenicity prediction, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.129 | Likely Benign | 0.862 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.59 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.38 | Pathogenic | 0.48 | Tolerated | 0.1614 | 0.4244 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3559A>C | M1187L 2D AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3559A>T | M1187L 2D AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign effect for M1187L, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3683A>T | E1228V 2D AIThe SynGAP1 missense variant E1228V is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus score, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further separate the evidence: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus, derived from a consensus of four high‑confidence predictors, flags the variant as pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this change. Overall, the preponderance of pathogenic predictions, including the SGM‑Consensus, outweighs the benign calls. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -8.077 | Likely Pathogenic | 0.440 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -4.55 | Deleterious | 0.980 | Probably Damaging | 0.833 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0470 | 0.4252 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.2756A>C | Q919P 2D AIThe SynGAP1 missense variant Q919P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -2.358 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.15 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.38 | Pathogenic | 0.03 | Affected | 0.2364 | 0.6108 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>C | Q920P 2D AIThe SynGAP1 missense variant Q920P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -2.127 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -1.68 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.58 | Benign | 0.00 | Affected | 0.2438 | 0.5318 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2846G>T | G949V 2D AIThe SynGAP1 missense variant G949V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -7.364 | In-Between | 0.102 | Likely Benign | Likely Benign | 0.328 | Likely Benign | -0.55 | Neutral | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.21 | Pathogenic | 0.01 | Affected | 0.1493 | 0.3165 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3266G>A | G1089E 2D AIThe SynGAP1 missense variant G1089E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -3.233 | Likely Benign | 0.926 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.85 | Deleterious | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1460 | 0.4387 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.1907T>A | F636Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F636Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a pathogenic outcome (3/4 votes). High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. Stability‑based tools FoldX, Rosetta, and premPS are uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -9.638 | Likely Pathogenic | 0.695 | Likely Pathogenic | Likely Benign | 0.84 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.68 | Ambiguous | 0.90 | Ambiguous | 0.394 | Likely Benign | -2.89 | Deleterious | 0.927 | Possibly Damaging | 0.836 | Possibly Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1297 | 0.1866 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.2996C>T | S999F 2D AIThe SynGAP1 missense variant S999F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.206 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.79 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.0865 | 0.6337 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3770C>T | S1257F 2D AIThe SynGAP1 missense variant S1257F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.584 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 0.141 | Likely Benign | -2.41 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.55 | Benign | 0.08 | Tolerated | 0.0453 | 0.4747 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.1220A>T | Q407L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Four tools are uncertain (AlphaMissense‑Default, FoldX, Rosetta, Foldetta). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools predict pathogenicity than benign, and the high‑accuracy consensus leans pathogenic. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -12.730 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | -0.65 | Ambiguous | 0.2 | -0.69 | Ambiguous | -0.67 | Ambiguous | 0.35 | Likely Benign | 0.359 | Likely Benign | -6.32 | Deleterious | 0.939 | Possibly Damaging | 0.838 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.0585 | 0.4977 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.1610C>A | A537E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | -5.120 | Likely Benign | 0.450 | Ambiguous | Likely Benign | -0.14 | Likely Benign | 0.1 | 0.00 | Likely Benign | -0.07 | Likely Benign | 0.23 | Likely Benign | 0.378 | Likely Benign | -1.78 | Neutral | 0.987 | Probably Damaging | 0.838 | Possibly Damaging | -1.04 | Pathogenic | 1.00 | Tolerated | 0.1347 | 0.1566 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||
| c.2105A>T | Q702L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the balance of evidence leans toward a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -9.954 | Likely Pathogenic | 0.149 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.0 | 0.09 | Likely Benign | -0.02 | Likely Benign | 0.16 | Likely Benign | 0.392 | Likely Benign | -5.66 | Deleterious | 0.939 | Possibly Damaging | 0.838 | Possibly Damaging | 3.42 | Benign | 0.00 | Affected | 0.0584 | 0.3628 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.1925A>C | K642T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642T is listed in ClinVar (ID 437411.0) as Pathogenic and is not reported in gnomAD. Functional prediction tools split in a 7‑to‑5 ratio: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while benign calls come from REVEL, Rosetta, Foldetta, premPS, and FATHMM; FoldX and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as Benign. Overall, the majority of evidence points to a pathogenic effect, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | Likely Pathogenic | 1 | -12.823 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.53 | Ambiguous | 0.1 | 0.30 | Likely Benign | 0.42 | Likely Benign | 0.28 | Likely Benign | 0.484 | Likely Benign | -5.88 | Deleterious | 0.872 | Possibly Damaging | 0.839 | Possibly Damaging | 2.86 | Benign | 0.00 | Affected | 3.37 | 31 | 0.1899 | 0.3270 | 0 | -1 | 3.2 | -27.07 | 213.5 | -8.7 | -0.3 | 0.4 | 0.3 | 0.2 | X | Uncertain | The amino side chain of Lys642, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the shorter side chain of Thr642 forms hydrogen bonds with Glu643 and Thr640 on the same α helix.Regardless, Lys642 is positioned directly at the GAP-Ras interface, and in the SynGAP-Ras WT simulations, its amino side chain forms salt bridges with the carboxylate groups of Ras residues Asp33 and Asp38. The shorter Thr642 is more likely to prefer hydrogen bonding with Glu643 and Thr640 on the same α helix, even in the Ras complex. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be explored using solvent-only simulations. | ||||||||||||||||
| c.2042G>A | G681D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas the remaining 11 tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict pathogenicity. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized returns a pathogenic classification; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. premPS is inconclusive and is treated as unavailable. Taken together, the overwhelming majority of evidence points to a pathogenic impact for G681D. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -12.451 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 1.5 | 4.54 | Destabilizing | 3.58 | Destabilizing | 0.96 | Ambiguous | 0.471 | Likely Benign | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.840 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0.1697 | 0.1695 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.2398G>T | G800C 2D AIThe SynGAP1 missense variant G800C is not reported in ClinVar and has no allele in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a benign outcome; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of a ClinVar pathogenic annotation. Based on the aggregate predictions, the variant is most likely benign, and this is consistent with the lack of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -7.074 | In-Between | 0.129 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -1.53 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 2.70 | Benign | 0.15 | Tolerated | 0.1102 | 0.4189 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.251G>A | R84H 2D AIThe SynGAP1 missense variant R84H is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available output. Overall, the majority of standard predictors (four pathogenic vs. three benign) lean toward a pathogenic interpretation, and the high‑accuracy consensus does not overturn this trend. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.529205 | Binding | 0.298 | 0.888 | 0.500 | -7.333 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | -1.77 | Neutral | 0.995 | Probably Damaging | 0.840 | Possibly Damaging | 3.68 | Benign | 0.00 | Affected | 0.2739 | 0.2426 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2842G>T | G948C 2D AIThe SynGAP1 missense variant G948C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict ClinVar status, as no ClinVar assertion exists for this variant. Thus, based on the available computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -10.254 | Likely Pathogenic | 0.102 | Likely Benign | Likely Benign | 0.247 | Likely Benign | -0.77 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 4.50 | Benign | 0.04 | Affected | 0.1422 | 0.4439 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2927T>G | F976C 2D AIThe SynGAP1 missense variant F976C is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for F976C, and this conclusion is not in conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -5.490 | Likely Benign | 0.490 | Ambiguous | Likely Benign | 0.103 | Likely Benign | -1.10 | Neutral | 0.977 | Probably Damaging | 0.840 | Possibly Damaging | 4.09 | Benign | 0.10 | Tolerated | 0.2961 | 0.2505 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.301C>G | H101D 2D  AIThe SynGAP1 missense variant H101D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is not in conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.788 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.49 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.2479 | 0.2272 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.302A>G | H101R 2D  AIThe SynGAP1 missense variant H101R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H101R, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.685 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -0.76 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 0.1891 | 0.2225 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.302A>T | H101L 2D  AIThe SynGAP1 missense variant H101L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H101L, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -1.376 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.129 | Likely Benign | -1.33 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.19 | Benign | 0.00 | Affected | 0.0924 | 0.4960 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3218C>G | S1073C 2D AISynGAP1 missense variant S1073C is recorded in gnomAD (ID 6‑33443770‑C‑G) but has no ClinVar submission. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The AlphaMissense‑Default score is uncertain. A consensus from the SGM framework (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because the votes are split. High‑accuracy methods give a benign prediction from AlphaMissense‑Optimized; the SGM Consensus remains ambiguous, and Foldetta stability analysis is unavailable. Consequently, the evidence does not strongly favor either outcome. The variant is most likely of uncertain significance, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | 6-33443770-C-G | 1 | 6.23e-7 | -8.862 | Likely Pathogenic | 0.461 | Ambiguous | Likely Benign | 0.137 | Likely Benign | -1.52 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1343 | 0.6088 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3251C>A | P1084H 2D AIThe SynGAP1 missense variant P1084H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443803‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which reports “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Thus, the variant is most likely benign, and its prediction profile does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | Uncertain | 1 | 6-33443803-C-A | 1 | 6.31e-7 | -4.125 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -3.16 | Deleterious | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1751 | 0.5523 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.3260C>G | S1087C 2D AIThe SynGAP1 missense variant S1087C is catalogued in gnomAD (ID 6‑33443812‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-G | 1 | 6.34e-7 | -7.369 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -2.22 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.55 | Benign | 0.05 | Affected | 3.77 | 5 | 0.0979 | 0.6118 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.3296A>G | Y1099C 2D AIThe SynGAP1 missense variant Y1099C is reported in gnomAD (variant ID 6‑33443848‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443848-A-G | 3 | 1.95e-6 | -5.670 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.13 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.73 | Benign | 0.14 | Tolerated | 3.77 | 5 | 0.3008 | 0.2382 | -2 | 0 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||||
| c.3349G>T | G1117C 2D AIThe SynGAP1 missense variant G1117C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -9.045 | Likely Pathogenic | 0.112 | Likely Benign | Likely Benign | 0.359 | Likely Benign | -1.30 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 4.56 | Benign | 0.03 | Affected | 0.1347 | 0.4612 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3358G>T | G1120C 2D AIThe SynGAP1 missense variant G1120C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for G1120C, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -9.324 | Likely Pathogenic | 0.112 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -1.32 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 3.60 | Benign | 0.03 | Affected | 0.1271 | 0.4227 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3361A>T | S1121C 2D AIThe SynGAP1 missense variant S1121C is listed in gnomAD (ID 6‑33443913‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | 6-33443913-A-T | -7.431 | In-Between | 0.094 | Likely Benign | Likely Benign | 0.354 | Likely Benign | -0.99 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 5.43 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1705 | 0.5691 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3367G>T | G1123C 2D AIThe SynGAP1 missense variant G1123C is listed in gnomAD (ID 6‑33443919‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy tools—supports a benign classification. This conclusion is not contradicted by ClinVar, which contains no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | 6-33443919-G-T | 1 | 6.64e-7 | -9.329 | Likely Pathogenic | 0.118 | Likely Benign | Likely Benign | 0.353 | Likely Benign | -1.17 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 4.34 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1348 | 0.4227 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.3899C>A | P1300H 2D AIThe SynGAP1 missense variant P1300H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -5.062 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.48 | Neutral | 0.990 | Probably Damaging | 0.840 | Possibly Damaging | 2.80 | Benign | 0.01 | Affected | 0.1757 | 0.3802 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.391G>T | G131C 2D AIThe SynGAP1 missense variant G131C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus again indicates Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of tools predict pathogenicity, and this aligns with the SGM Consensus. Therefore, the variant is most likely pathogenic based on the available predictions, and this conclusion is consistent with the lack of ClinVar reporting rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -8.288 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -4.42 | Deleterious | 0.998 | Probably Damaging | 0.840 | Possibly Damaging | 3.88 | Benign | 0.00 | Affected | 0.1339 | 0.4356 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.460A>T | S154C 2D AIThe SynGAP1 missense variant S154C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and Foldetta results are unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. With the majority of evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -7.728 | In-Between | 0.244 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.841 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 0.1288 | 0.5042 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.690C>G | C230W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by FATHMM and FoldX, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic impact for C230W, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -11.022 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.21 | Likely Benign | 0.0 | -1.87 | Ambiguous | -1.04 | Ambiguous | 0.74 | Ambiguous | 0.739 | Likely Pathogenic | -8.79 | Deleterious | 0.983 | Probably Damaging | 0.841 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0.1589 | 0.3663 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.2956G>C | E986Q 2D AIThe SynGAP1 missense variant E986Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.471 | Likely Benign | 0.839 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -1.66 | Neutral | 0.974 | Probably Damaging | 0.842 | Possibly Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.1700 | 0.7589 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.1370G>A | S457N 2D AIThe SynGAP1 missense variant S457N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy Foldetta result suggests a benign impact. Thus, the variant is most likely pathogenic based on the preponderance of predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | Uncertain | 1 | -10.221 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | 0.241 | Likely Benign | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 0.1015 | 0.4980 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.3724G>C | E1242Q 2D AIThe SynGAP1 missense variant E1242Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Consequently, the aggregate evidence favors a benign effect for E1242Q, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.557691 | Disordered | 0.456349 | Uncertain | 0.870 | 0.549 | 0.500 | -7.036 | In-Between | 0.291 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.33 | Neutral | 0.969 | Probably Damaging | 0.843 | Possibly Damaging | 2.21 | Pathogenic | 0.00 | Affected | 0.0763 | 0.3666 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1034T>A | L345Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L345Q is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into benign (REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM). FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of predictions lean toward pathogenicity, while the single high‑accuracy tool that is definitive is benign. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -6.034 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.1 | 0.86 | Ambiguous | 1.09 | Ambiguous | 1.26 | Destabilizing | 0.218 | Likely Benign | -3.67 | Deleterious | 0.993 | Probably Damaging | 0.844 | Possibly Damaging | 1.82 | Pathogenic | 0.03 | Affected | 0.0937 | 0.0842 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
| c.1136C>G | S379W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | 0.520 | Likely Pathogenic | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | 0.1196 | 0.6070 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 0.5 | Uncertain | Ser379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn | |||||||||||||||||
| c.1525G>C | A509P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -13.234 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 5.82 | Destabilizing | 0.6 | 7.70 | Destabilizing | 6.76 | Destabilizing | 1.13 | Destabilizing | 0.884 | Likely Pathogenic | -4.15 | Deleterious | 0.987 | Probably Damaging | 0.844 | Possibly Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1940 | 0.4570 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1526C>A | A509D 2D AIThe SynGAP1 missense variant A509D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -17.026 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 1.6 | 3.09 | Destabilizing | 3.56 | Destabilizing | 1.36 | Destabilizing | 0.915 | Likely Pathogenic | -4.94 | Deleterious | 0.963 | Probably Damaging | 0.844 | Possibly Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.1610 | 0.1360 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.2060G>A | R687Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R687Q is annotated in ClinVar as benign (ClinVar ID 2693600.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, SGM‑Consensus indicating pathogenicity, and Foldetta (integrating FoldX‑MD and Rosetta outputs) classifying it as benign. With three high‑accuracy tools giving benign or uncertain results and only one (SGM‑Consensus) suggesting pathogenicity, the overall evidence leans toward a benign effect. This prediction aligns with the ClinVar benign classification, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | Likely Benign | 1 | -10.002 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.92 | Ambiguous | 0.1 | -0.37 | Likely Benign | 0.28 | Likely Benign | 1.55 | Destabilizing | 0.401 | Likely Benign | -3.37 | Deleterious | 1.000 | Probably Damaging | 0.844 | Possibly Damaging | 3.91 | Benign | 0.03 | Affected | 3.42 | 17 | 0.2143 | 0.1952 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||
| c.314C>G | S105W 2D AIThe SynGAP1 missense variant S105W is catalogued in gnomAD (ID 6‑33432179‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | 6-33432179-C-G | 2 | 1.24e-6 | -5.600 | Likely Benign | 0.606 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -2.28 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0705 | 0.4984 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3056G>A | R1019H 2D AIThe SynGAP1 missense variant R1019H is listed in ClinVar (ID 1195115.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443608‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for R1019H, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Conflicting | 2 | 6-33443608-G-A | 67 | 4.15e-5 | -4.610 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.95 | Neutral | 0.995 | Probably Damaging | 0.845 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2400 | 0.1903 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.2291A>G | N764S 2D  AIThe SynGAP1 missense variant N764S is listed in ClinVar as Benign (ClinVar ID 1948460.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, consistent with the ClinVar classification, and there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | Benign | 1 | -3.149 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.84 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.61 | Tolerated | 3.64 | 6 | 0.3762 | 0.5062 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||
| c.2446T>A | S816T 2D AIThe SynGAP1 missense variant S816T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.957 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.064 | Likely Benign | -1.05 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.32 | Tolerated | 0.1573 | 0.5529 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2449T>A | S817T 2D AIThe SynGAP1 missense variant S817T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign, and Foldetta results are unavailable. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign impact for S817T. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.544 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.95 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1622 | 0.6482 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2449T>G | S817A 2D AIThe SynGAP1 missense variant S817A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign, while Foldetta results are unavailable. Overall, the majority of high‑confidence predictions indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.321 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -1.86 | Neutral | 0.977 | Probably Damaging | 0.846 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.5207 | 0.5866 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2573G>A | S858N 2D AIThe SynGAP1 missense variant S858N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443125‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 HumVar and SIFT predict pathogenicity, but these two tools are in the minority. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | Uncertain | 1 | 6-33443125-G-A | 2 | 1.24e-6 | -4.311 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -0.67 | Neutral | 0.448 | Benign | 0.846 | Possibly Damaging | 4.13 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1527 | 0.4772 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
| c.2704G>C | A902P 2D AIThe SynGAP1 missense variant A902P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A902P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -4.509 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.146 | Likely Benign | 0.09 | Neutral | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1694 | 0.5304 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2720G>C | S907T 2D AIThe SynGAP1 missense variant S907T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -4.794 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.53 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.66 | Benign | 0.93 | Tolerated | 0.1324 | 0.6352 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3532T>G | Y1178D 2D AIThe SynGAP1 missense variant Y1178D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized yields an Uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence from high‑accuracy tools and consensus predictions leans toward a benign classification. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -1.250 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.434 | Likely Benign | -1.33 | Neutral | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 5.55 | Benign | 0.07 | Tolerated | 0.4562 | 0.0173 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.3812A>T | E1271V 2D AISynGAP1 missense variant E1271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Considering the majority of high‑confidence tools and the consensus score, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -6.961 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.303 | Likely Benign | -5.64 | Deleterious | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.0620 | 0.6106 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>T | G1303V 2D AIThe SynGAP1 missense variant G1303V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.513 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -2.44 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.79 | Benign | 0.02 | Affected | 0.1511 | 0.3508 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.1760G>C | R587T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R587T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain predictions from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R587T, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | Uncertain | 1 | -9.697 | Likely Pathogenic | 0.784 | Likely Pathogenic | Likely Benign | 1.14 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.94 | Ambiguous | 0.98 | Ambiguous | 0.603 | Likely Pathogenic | -4.71 | Deleterious | 0.998 | Probably Damaging | 0.847 | Possibly Damaging | -1.19 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | 0.1958 | 0.4578 | -1 | -1 | 3.8 | -55.08 | 227.2 | 87.4 | 0.0 | 0.0 | 0.5 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg587, located on an α helix (res. Glu582-Met603), is constantly rotating and breaking/forming multiple hydrogen bonds and/or salt bridges at the surface intersection of α helices in the WT simulations. The positively charged Arg587 side chain can form a salt bridge with either the carboxylate group of Asp583 or Asp586 in the same helix, or with Glu480 on the opposing short helical loop structure (res. Glu480-Leu482).Importantly, the Arg587 side chain also hydrogen bonds with the backbone carbonyl groups of Ala634 and Asn635, as well as the carboxamide group of Asn635 at the end of another α helix (res. Asp616-Phe636). However, in the variant simulations, the neutral hydroxyl group of the Thr587 side chain is unable to form these salt bridges. Due to its smaller size, it also does not form the hydrogen bonds that the Arg587 side chain could. Instead, the hydroxyl group of Thr587 hydrogen bonds with the backbone carbonyl group of Asp583, which could weaken the integrity of the α helix, although this is not observed in the simulations.Overall, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | ||||||||||||||||
| c.475A>C | I159L 2D AIThe SynGAP1 missense variant I159L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for I159L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -7.936 | In-Between | 0.195 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.39 | Neutral | 0.904 | Possibly Damaging | 0.847 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 0.0776 | 0.2652 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.475A>G | I159V 2D AIThe SynGAP1 I159V missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.714 | Likely Pathogenic | 0.384 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -0.25 | Neutral | 0.803 | Possibly Damaging | 0.847 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.1111 | 0.2736 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.122G>A | R41H 2D AIThe SynGAP1 missense variant R41H is reported in gnomAD (variant ID 6-33423531‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: the majority (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a benign effect, while a minority (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. No Foldetta stability data are available, so it does not influence the overall assessment. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.311707 | Structured | 0.431757 | Uncertain | 0.344 | 0.765 | 0.375 | 6-33423531-G-A | 6 | 3.72e-6 | -4.425 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.74 | Neutral | 0.976 | Probably Damaging | 0.848 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3388 | 0.3065 | 0 | 2 | 1.3 | -19.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.2585A>G | N862S 2D AIThe SynGAP1 missense variant at residue 862 (N862S) is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -3.650 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.40 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 4.13 | Benign | 0.36 | Tolerated | 0.3809 | 0.7198 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>A | D868E 2D AIThe SynGAP1 missense variant D868E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>G | D868E 2D AIThe SynGAP1 missense variant D868E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2830G>T | G944C 2D AIThe SynGAP1 missense variant G944C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443382‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote of the four contributing tools) also indicates Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | 6-33443382-G-T | 1 | 6.20e-7 | -9.121 | Likely Pathogenic | 0.093 | Likely Benign | Likely Benign | 0.426 | Likely Benign | -1.79 | Neutral | 0.975 | Probably Damaging | 0.848 | Possibly Damaging | 3.70 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1399 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.3050T>C | F1017S 2D  AIThe SynGAP1 missense variant F1017S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -1.804 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -3.16 | Deleterious | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.4491 | 0.0000 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>C | G1113R 2D AIThe SynGAP1 missense variant G1113R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.765 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.063 | Likely Benign | -1.54 | Neutral | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.65 | Benign | 0.64 | Tolerated | 0.0939 | 0.4426 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3883C>G | Q1295E 2D  AIThe SynGAP1 missense variant Q1295E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -3.192 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.264 | Likely Benign | -2.46 | Neutral | 0.843 | Possibly Damaging | 0.848 | Possibly Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1428 | 0.1492 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1291C>A | L431M 2D AIThe SynGAP1 missense variant L431M (ClinVar ID 4327026) is not found in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and Foldetta, whereas premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT all predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No predictions or stability results are missing or inconclusive. Overall, the majority of computational evidence indicates that the variant is most likely benign, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | 1 | -7.471 | In-Between | 0.375 | Ambiguous | Likely Benign | 0.18 | Likely Benign | 0.3 | 0.50 | Ambiguous | 0.34 | Likely Benign | 1.07 | Destabilizing | 0.102 | Likely Benign | -1.50 | Neutral | 0.995 | Probably Damaging | 0.849 | Possibly Damaging | 2.94 | Benign | 0.02 | Affected | 0.0748 | 0.3121 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1381G>C | A461P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -13.869 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.1 | 5.09 | Destabilizing | 2.37 | Destabilizing | 0.84 | Ambiguous | 0.451 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.32 | Benign | 0.03 | Affected | 0.1748 | 0.3949 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.508C>T | R170W 2D AIThe SynGAP1 missense variant R170W is listed in ClinVar (ID 1310195.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Uncertain | 2 | -11.660 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.241 | Likely Benign | -4.28 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.84 | Benign | 0.00 | Affected | 3.74 | 4 | 0.1026 | 0.3469 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.2249G>T | G750V 2D AIThe SynGAP1 missense variant G750V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show AlphaMissense‑Optimized as benign, while the remaining high‑confidence tools (PROVEAN, polyPhen‑2, SIFT, FATHMM) all indicate pathogenicity. Overall, the majority of evidence (five pathogenic vs four benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -4.512 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.54 | Deleterious | 0.984 | Probably Damaging | 0.850 | Possibly Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.1270 | 0.4212 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2291A>C | N764T 2D AIThe SynGAP1 missense variant N764T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -4.214 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.071 | Likely Benign | -1.57 | Neutral | 0.975 | Probably Damaging | 0.850 | Possibly Damaging | 2.63 | Benign | 0.05 | Affected | 0.1272 | 0.5168 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3196C>T | P1066S 2D AIThe SynGAP1 missense variant P1066S is listed in ClinVar as Pathogenic (ClinVar ID 1343237.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, which contradicts the ClinVar pathogenic classification. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | Likely Pathogenic | 1 | -4.746 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.47 | Neutral | 0.972 | Probably Damaging | 0.850 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3304 | 0.6353 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.1217A>G | Y406C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome, and the Foldetta stability assessment (combining FoldX‑MD and Rosetta) predicts a destabilizing, pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while both SGM‑Consensus and Foldetta are pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for Y406C, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.954 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 0.2 | 3.22 | Destabilizing | 2.85 | Destabilizing | 1.27 | Destabilizing | 0.229 | Likely Benign | -6.72 | Deleterious | 0.998 | Probably Damaging | 0.851 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 0.3026 | 0.2861 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1300G>A | V434I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434I (ClinVar ID 212346.0, status Uncertain) is present in gnomAD (ID 6‑33438205‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | Uncertain | 1 | 6-33438205-G-A | 1 | 6.19e-7 | -6.999 | Likely Benign | 0.129 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.09 | Likely Benign | 0.31 | Likely Benign | 0.192 | Likely Benign | -0.82 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.53 | Benign | 0.18 | Tolerated | 3.37 | 29 | 0.0675 | 0.3415 | 4 | 3 | 0.3 | 14.03 | 246.7 | -27.7 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Benign | The iso-propyl side chain of Val434, located at the end of an α helix (res. Met414-Glu436), packs against hydrophobic residues in an interhelix space (e.g., Met430, Ala707, Leu711). In the variant simulations, the sec-butyl group of Ile434 is able to form the same hydrophobic interactions. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | |||||||||||||
| c.1300G>C | V434L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools, Rosetta and AlphaMissense‑Default, give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, a protein‑folding stability method, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V434L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.697 | Likely Pathogenic | 0.477 | Ambiguous | Likely Benign | -0.05 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.49 | Likely Benign | 0.20 | Likely Benign | 0.225 | Likely Benign | -2.30 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.64 | Benign | 0.27 | Tolerated | 0.0895 | 0.3813 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1339G>A | V447I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Thus, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -5.067 | Likely Benign | 0.167 | Likely Benign | Likely Benign | -0.33 | Likely Benign | 0.1 | 0.27 | Likely Benign | -0.03 | Likely Benign | -0.44 | Likely Benign | 0.117 | Likely Benign | -0.06 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.37 | Benign | 0.28 | Tolerated | 0.0625 | 0.3059 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.1339G>C | V447L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | 0.180 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 0.0757 | 0.3477 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1354G>A | V452I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | 0.218 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 0.0630 | 0.3476 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||
| c.1354G>C | V452L 2D 3DClick to see structure in 3D Viewer AISynGAP1 V452L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Because the majority of tools (six) predict benign and the high‑accuracy Foldetta also supports benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -11.285 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | -0.25 | Likely Benign | 0.02 | Likely Benign | 0.34 | Likely Benign | 0.316 | Likely Benign | -2.96 | Deleterious | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.54 | Benign | 0.11 | Tolerated | 0.0777 | 0.4061 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1387G>C | D463H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D463H is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, SGM Consensus confirms Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. No evidence from ClinVar contradicts these findings. Overall, the preponderance of computational evidence indicates that D463H is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -13.151 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.53 | Ambiguous | 0.57 | Ambiguous | 0.356 | Likely Benign | -5.96 | Deleterious | 0.996 | Probably Damaging | 0.852 | Possibly Damaging | 3.35 | Benign | 0.11 | Tolerated | 0.1341 | 0.6156 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.2242C>A | L748M 2D AIThe SynGAP1 missense variant L748M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.611637 | Binding | 0.339 | 0.863 | 0.750 | -3.935 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.12 | Neutral | 0.991 | Probably Damaging | 0.852 | Possibly Damaging | 2.70 | Benign | 0.05 | Affected | 0.0909 | 0.3863 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.4000A>T | N1334Y 2D AIThe SynGAP1 missense variant N1334Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive; Foldetta results are unavailable. Overall, the majority of conventional tools predict a pathogenic impact, but the single high‑accuracy benign prediction and the inconclusive consensus suggest uncertainty. Consequently, the variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict any ClinVar annotation because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -5.916 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | -4.62 | Deleterious | 0.985 | Probably Damaging | 0.852 | Possibly Damaging | 3.49 | Benign | 0.00 | Affected | 0.0716 | 0.5447 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.1771G>C | A591P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A591P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely converge on a pathogenic effect: pathogenic predictions come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Consequently, the variant is most likely pathogenic, a conclusion that contrasts with its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | Uncertain | 1 | -14.479 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.78 | Destabilizing | 0.3 | 7.29 | Destabilizing | 5.54 | Destabilizing | 1.45 | Destabilizing | 0.404 | Likely Benign | -4.41 | Deleterious | 0.995 | Probably Damaging | 0.853 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 3.37 | 35 | 0.1872 | 0.3087 | 1 | -1 | -3.4 | 26.04 | 191.5 | -10.1 | 0.2 | 0.1 | 0.4 | 0.1 | X | Potentially Pathogenic | The methyl group of the Ala591 side chain, located in the middle of an α helix (res. Glu582-Met603), packs against hydrophobic residues (e.g., Ile483, Phe484) of an opposing partially helical loop (res. Phe476-Asn487).In the variant simulations, Pro591 lacks a free backbone amide group and, therefore, cannot form a hydrogen bond with the backbone carbonyl of Arg587 as Ala591 does in the WT. This notably weakens the α helix integrity and compromises the continuity of the helix. In reality, the effect on the structure during protein folding could be more severe. | ||||||||||||||||
| c.1528A>T | I510F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact; Rosetta remains uncertain. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -8.185 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 4.66 | Destabilizing | 0.7 | 1.38 | Ambiguous | 3.02 | Destabilizing | 0.50 | Likely Benign | 0.692 | Likely Pathogenic | -2.64 | Deleterious | 0.991 | Probably Damaging | 0.854 | Possibly Damaging | -1.14 | Pathogenic | 0.01 | Affected | 0.0552 | 0.1794 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1535A>T | E512V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -14.011 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.1 | 1.00 | Ambiguous | 0.86 | Ambiguous | 0.14 | Likely Benign | 0.439 | Likely Benign | -6.71 | Deleterious | 0.989 | Probably Damaging | 0.854 | Possibly Damaging | 3.23 | Benign | 0.01 | Affected | 0.0994 | 0.4884 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.724T>A | W242R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant W242R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | 0.859 | Likely Pathogenic | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | 0.4206 | 0.0771 | -3 | 2 | -3.6 | -30.03 | |||||||||||||||||||||||||||
| c.724T>C | W242R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242R is reported in gnomAD (ID 6‑33435575‑T‑C) but has no ClinVar entry. Across the evaluated predictors, every tool that provides a definitive call classifies the substitution as pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No predictor reports a benign effect. FoldX, Rosetta, and Foldetta return uncertain results and are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | 6-33435575-T-C | 2 | 1.24e-6 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | 0.858 | Likely Pathogenic | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | 0.4206 | 0.0771 | -3 | 2 | -3.6 | -30.03 | ||||||||||||||||||||||||
| c.728T>A | I243N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I243N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign (FATHMM), pathogenic (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized), and uncertain (FoldX, Rosetta, Foldetta). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -14.784 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 1.90 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.67 | Ambiguous | 1.76 | Destabilizing | 0.811 | Likely Pathogenic | -4.46 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.0899 | 0.0212 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.741G>C | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SGM‑Consensus, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Tools that predict a pathogenic outcome are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.741G>T | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Those that predict a pathogenic impact are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall balance of evidence—seven benign versus five pathogenic predictions, and all high‑accuracy tools indicating benign—the variant is most likely benign. This conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.2440G>C | A814P 2D AIThe SynGAP1 missense variant A814P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for A814P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.247 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.210 | Likely Benign | -1.88 | Neutral | 0.984 | Probably Damaging | 0.855 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 0.1845 | 0.4941 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2297C>A | S766Y 2D AIThe SynGAP1 missense variant S766Y is reported in gnomAD (ID 6‑33442455‑C‑A) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote) predicts pathogenic, and no Foldetta stability data are available. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-A | -8.636 | Likely Pathogenic | 0.641 | Likely Pathogenic | Likely Benign | 0.222 | Likely Benign | -2.67 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0794 | 0.5609 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.2297C>T | S766F 2D AIThe SynGAP1 missense variant S766F is listed in gnomAD (ID 6‑33442455‑C‑T) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-T | -8.944 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 0.233 | Likely Benign | -2.87 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0770 | 0.5887 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.2437C>G | L813V 2D AIThe SynGAP1 missense variant L813V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.809 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.98 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 2.62 | Benign | 0.28 | Tolerated | 0.1704 | 0.3744 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2506A>C | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence (five benign versus three pathogenic predictions, with the high‑accuracy consensus leaning benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2508T>A | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2508T>G | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Grouping by agreement, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Benign, and no Foldetta stability data are available. Overall, the preponderance of evidence leans toward a benign effect for S836R, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2542G>C | G848R 2D AIThe SynGAP1 missense variant G848R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G848R, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -4.867 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.05 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.0952 | 0.4251 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2543G>T | G848V 2D AIThe SynGAP1 missense variant G848V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443095‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | 6-33443095-G-T | 1 | 6.20e-7 | -4.445 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1184 | 0.4336 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.2689T>C | S897P 2D AIThe SynGAP1 missense variant S897P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.418474 | Uncertain | 0.292 | 0.928 | 0.500 | -4.088 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.21 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.64 | Benign | 0.04 | Affected | 0.2014 | 0.5933 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2734A>G | T912A 2D AIThe SynGAP1 missense variant T912A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -3.084 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.50 | Neutral | 0.973 | Probably Damaging | 0.856 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | 0.3754 | 0.3841 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2734A>T | T912S 2D AIThe SynGAP1 missense variant T912S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for T912S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -2.647 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.05 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.3078 | 0.3893 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2735C>G | T912S 2D AIThe SynGAP1 missense variant T912S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for T912S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -2.647 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -1.05 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.3078 | 0.3893 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>A | P954T 2D AIThe SynGAP1 missense variant P954T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.657 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.77 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.79 | Benign | 0.48 | Tolerated | 0.1860 | 0.6324 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2944T>G | Y982D 2D AIThe SynGAP1 missense variant Y982D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.966717 | Binding | 0.272 | 0.895 | 0.625 | -5.021 | Likely Benign | 0.952 | Likely Pathogenic | Ambiguous | 0.194 | Likely Benign | -1.29 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 0.3959 | 0.0545 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3047A>T | D1016V 2D AIThe SynGAP1 D1016V missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give an uncertain result from AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no available data from Foldetta. Overall, the majority of evidence points toward a deleterious effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.208 | Likely Benign | 0.800 | Likely Pathogenic | Ambiguous | 0.362 | Likely Benign | -3.80 | Deleterious | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.1424 | 0.7116 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3281C>A | S1094Y 2D AIThe SynGAP1 missense variant S1094Y is not reported in ClinVar (status: none) but is present in gnomAD (ID 6‑33443833‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show a benign call from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the balance of evidence leans toward a pathogenic interpretation (five pathogenic versus four benign calls), and this does not contradict the ClinVar status, which currently has no assertion for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | 6-33443833-C-A | -5.609 | Likely Benign | 0.631 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -2.07 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1007 | 0.5877 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||
| c.3281C>T | S1094F 2D AIThe SynGAP1 missense variant S1094F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -5.655 | Likely Benign | 0.666 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | -2.17 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.0925 | 0.5851 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3578A>T | D1193V 2D AIThe SynGAP1 D1193V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic vs. one benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -7.297 | In-Between | 0.855 | Likely Pathogenic | Ambiguous | 0.526 | Likely Pathogenic | -2.92 | Deleterious | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 5.51 | Benign | 0.00 | Affected | 0.0752 | 0.4174 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3610T>C | S1204P 2D AIThe SynGAP1 missense variant S1204P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S1204P. This prediction does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | -14.031 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.502 | Likely Pathogenic | -1.80 | Neutral | 0.988 | Probably Damaging | 0.856 | Possibly Damaging | 5.39 | Benign | 0.31 | Tolerated | 0.2139 | 0.3886 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3872T>A | L1291Q 2D AISynGAP1 missense variant L1291Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is equivocal (two benign, two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence is split, with an equal number of benign and pathogenic calls and no decisive high‑accuracy consensus. Consequently, the variant’s likely effect remains uncertain; it is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -4.450 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -4.18 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1052 | 0.1049 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3872T>C | L1291P 2D AIThe SynGAP1 missense variant L1291P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. Because there is no ClinVar assertion, this prediction does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -3.322 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.417 | Likely Benign | -4.32 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.3078 | 0.2162 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3872T>G | L1291R 2D AIThe SynGAP1 missense variant L1291R is not reported in ClinVar and is present in gnomAD (ID 6‑33447920‑T‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta results are unavailable. Overall, the majority of conventional predictors indicate a pathogenic effect, whereas the single high‑accuracy tool suggests benign. No ClinVar annotation contradicts these findings. Thus, based on the collective evidence, the variant is most likely pathogenic, though the high‑accuracy prediction introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447920-T-G | 1 | 6.44e-7 | -3.977 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.287 | Likely Benign | -4.29 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1160 | 0.1049 | -2 | -3 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.112C>G | P38A 2D AIThe SynGAP1 missense variant P38A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P38A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.433285 | Uncertain | 0.344 | 0.791 | 0.375 | -3.179 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -2.03 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.3888 | 0.5977 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.124C>G | P42A 2D AIThe SynGAP1 missense variant P42A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect for P42A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.308712 | Structured | 0.431487 | Uncertain | 0.420 | 0.771 | 0.375 | -3.945 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.27 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 4.32 | Benign | 0.00 | Affected | 0.3441 | 0.4323 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.136C>G | P46A 2D AIThe SynGAP1 missense variant P46A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P46A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | -4.811 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.68 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 4.16 | Benign | 0.00 | Affected | 0.3987 | 0.5696 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.178G>A | D60N 2D AIThe SynGAP1 D60N missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -3.610 | Likely Benign | 0.577 | Likely Pathogenic | Likely Benign | 0.128 | Likely Benign | -0.22 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.1219 | 0.8168 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.179A>C | D60A 2D AIThe SynGAP1 D60A missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evaluated tools lean toward a benign interpretation, with no evidence of pathogenicity from the high‑confidence methods. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none exists for this allele. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -4.500 | Likely Benign | 0.918 | Likely Pathogenic | Ambiguous | 0.167 | Likely Benign | -2.17 | Neutral | 0.909 | Possibly Damaging | 0.857 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 0.3851 | 0.7405 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.179A>G | D60G 2D AIThe SynGAP1 D60G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -4.423 | Likely Benign | 0.775 | Likely Pathogenic | Likely Benign | 0.128 | Likely Benign | -1.67 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.4143 | 0.7069 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.343C>A | Q115K 2D AIThe SynGAP1 missense variant Q115K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign interpretation: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) indicate pathogenic. When predictions are grouped by agreement, the benign‑oriented tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter the overall trend. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Based on the preponderance of benign predictions and the high‑accuracy consensus, the variant is most likely benign; this conclusion is consistent with the absence of a ClinVar pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.365 | Likely Benign | 0.507 | Ambiguous | Likely Benign | 0.101 | Likely Benign | -0.49 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.18 | Benign | 0.40 | Tolerated | 0.1704 | 0.3678 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.343C>G | Q115E 2D AIThe SynGAP1 missense variant Q115E is reported in gnomAD (variant ID 6‑33432208‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | 6-33432208-C-G | 1 | 6.20e-7 | -3.465 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.40 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.18 | Benign | 0.42 | Tolerated | 3.61 | 5 | 0.1377 | 0.1832 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.388C>A | Q130K 2D AIThe SynGAP1 missense variant Q130K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around benign: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification, whereas the pathogenic predictions come from polyPhen‑2 alone. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -4.656 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -0.41 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.20 | Benign | 0.07 | Tolerated | 0.2017 | 0.4473 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.388C>G | Q130E 2D AIThe SynGAP1 missense variant Q130E is reported in gnomAD (ID 6‑33432685‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | 6-33432685-C-G | 2 | 1.24e-6 | -4.283 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.72 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.1620 | 0.2587 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.3979C>T | P1327S 2D AIThe SynGAP1 missense variant P1327S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3098 | 0.4025 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.79C>G | P27A 2D AIThe SynGAP1 missense variant P27A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27A, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.409 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.98 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.4041 | 0.5219 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.1231A>G | I411V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411V is reported in ClinVar as benign (ClinVar ID 1654508.0) and is not found in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Two tools predict a pathogenic outcome: PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are AlphaMissense‑Default, FoldX, Rosetta, premPS, and Foldetta. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. Overall, the preponderance of evidence points to a benign effect for I411V, which is consistent with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | Likely Benign | 1 | -6.290 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.74 | Ambiguous | 0.0 | 0.82 | Ambiguous | 0.78 | Ambiguous | 0.99 | Ambiguous | 0.212 | Likely Benign | -0.86 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.90 | Benign | 0.27 | Tolerated | 3.38 | 28 | 0.1112 | 0.3526 | 4 | 3 | -0.3 | -14.03 | 233.3 | 28.2 | -0.2 | 0.0 | -0.2 | 0.0 | X | Potentially Benign | The sec-butyl side chain of Ile411, located in the hydrophobic space between an anti-parallel β sheet strand (res. Pro398-Ile411) and an α helix (res. Asp684-Gln702), packs against multiple residues (e.g., Met409, Arg259). In the variant simulations, the side chain of Val411 is able to favorably fill the same hydrophobic niche despite its slightly smaller size. In short, the residue swap has no apparent negative effect on the structure based on the simulations. | ||||||||||||||||
| c.1360A>G | I454V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as likely benign, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -4.719 | Likely Benign | 0.657 | Likely Pathogenic | Likely Benign | 1.47 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.42 | Ambiguous | 0.69 | Ambiguous | 0.132 | Likely Benign | -0.79 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.40 | Benign | 0.18 | Tolerated | 0.0833 | 0.2959 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.2411A>C | D804A 2D AIThe SynGAP1 D804A missense variant is catalogued in gnomAD (ID 6‑33442963‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | 6-33442963-A-C | -6.086 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.269 | Likely Benign | -3.99 | Deleterious | 0.980 | Probably Damaging | 0.858 | Possibly Damaging | 1.21 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3716 | 0.6824 | -2 | 0 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||
| c.2411A>G | D804G 2D AIThe SynGAP1 missense variant D804G is catalogued in gnomAD (ID 6‑33442963‑A‑G) but has no ClinVar entry. Prediction tools cluster into two groups: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | 6-33442963-A-G | 1 | 6.20e-7 | -5.051 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.287 | Likely Benign | -3.82 | Deleterious | 0.980 | Probably Damaging | 0.858 | Possibly Damaging | 1.21 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3854 | 0.6488 | -1 | 1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||
| c.209G>C | R70P 2D AIThe SynGAP1 missense variant R70P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.458981 | Uncertain | 0.392 | 0.793 | 0.375 | -2.914 | Likely Benign | 0.633 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -1.33 | Neutral | 0.989 | Probably Damaging | 0.859 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 0.1903 | 0.4304 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.251G>C | R84P 2D AIThe SynGAP1 missense variant R84P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b is uncertain and does not influence the consensus. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that R84P is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.529205 | Binding | 0.298 | 0.888 | 0.500 | -7.959 | In-Between | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.157 | Likely Benign | -2.50 | Deleterious | 0.989 | Probably Damaging | 0.859 | Possibly Damaging | 3.67 | Benign | 0.00 | Affected | 0.1978 | 0.4231 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.1241T>A | M414K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. FoldX and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is unavailable. Based on the overwhelming agreement among the majority of prediction tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.537 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.18 | Ambiguous | 0.1 | 2.39 | Destabilizing | 1.79 | Ambiguous | 1.50 | Destabilizing | 0.503 | Likely Pathogenic | -5.03 | Deleterious | 0.942 | Possibly Damaging | 0.860 | Possibly Damaging | 3.40 | Benign | 0.04 | Affected | 0.1299 | 0.0888 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.2065C>T | L689F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Two tools (Rosetta and premPS) yield uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -9.817 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 2.45 | Destabilizing | 0.2 | 1.95 | Ambiguous | 2.20 | Destabilizing | 0.67 | Ambiguous | 0.286 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.860 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.0608 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2516A>G | K839R 2D AIThe SynGAP1 missense variant K839R is catalogued in gnomAD (ID 6‑33443068‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for K839R, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | 6-33443068-A-G | 1 | 6.20e-7 | -7.111 | In-Between | 0.162 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.88 | Neutral | 0.972 | Probably Damaging | 0.860 | Possibly Damaging | 2.72 | Benign | 0.31 | Tolerated | 3.77 | 5 | 0.4823 | 0.1345 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||
| c.2603A>G | D868G 2D AIThe SynGAP1 missense variant D868G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM Consensus) – derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -2.218 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -2.71 | Deleterious | 0.986 | Probably Damaging | 0.860 | Possibly Damaging | 2.51 | Benign | 0.21 | Tolerated | 0.4658 | 0.6414 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.67G>C | D23H 2D AIThe SynGAP1 D23H missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.801 | Likely Benign | 0.867 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -2.46 | Neutral | 0.972 | Probably Damaging | 0.861 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 0.2644 | 0.9017 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.67G>T | D23Y 2D AIThe SynGAP1 D23Y missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33420331‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | 6-33420331-G-T | -4.191 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -2.87 | Deleterious | 0.972 | Probably Damaging | 0.861 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1013 | 0.7951 | -3 | -4 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||
| c.1504G>A | G502S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502S is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -11.357 | Likely Pathogenic | 0.616 | Likely Pathogenic | Likely Benign | 2.09 | Destabilizing | 0.6 | 0.71 | Ambiguous | 1.40 | Ambiguous | 0.96 | Ambiguous | 0.839 | Likely Pathogenic | -5.74 | Deleterious | 0.975 | Probably Damaging | 0.862 | Possibly Damaging | -1.64 | Pathogenic | 0.01 | Affected | 0.2429 | 0.3217 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2515A>C | K839Q 2D AIThe SynGAP1 missense variant K839Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions and the consensus call indicate a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -10.631 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -1.98 | Neutral | 0.972 | Probably Damaging | 0.862 | Possibly Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.4544 | 0.1437 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3587A>C | K1196T 2D AIThe SynGAP1 missense variant K1196T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -6.611 | Likely Benign | 0.828 | Likely Pathogenic | Ambiguous | 0.378 | Likely Benign | -2.17 | Neutral | 0.980 | Probably Damaging | 0.862 | Possibly Damaging | 5.36 | Benign | 0.04 | Affected | 0.1980 | 0.2452 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.1678G>A | V560M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V560M missense variant is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440730-G-A). Functional prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Uncertain predictions come from Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of high‑confidence tools predict a benign impact, with only one consensus pathogenic prediction. Therefore, the variant is most likely benign based on current computational evidence, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | Uncertain | 2 | 6-33440730-G-A | 15 | 9.50e-6 | -9.598 | Likely Pathogenic | 0.517 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.28 | Likely Benign | 0.72 | Ambiguous | 0.520 | Likely Pathogenic | -2.42 | Neutral | 0.999 | Probably Damaging | 0.863 | Possibly Damaging | -1.25 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0.1161 | 0.3980 | 2 | 1 | -2.3 | 32.06 | 234.9 | -52.6 | 0.0 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | Val560 is located on the surface at the end of an α-helix (res. Ala533-Val560). The iso-propyl group of Val560 favorably packs against Asp508 of the opposing α-helix (res. Gln503-Glu519). However, in the variant simulations, the bulkier thioether side chain of Met560 does not form equally favorable inter-helix interactions. Regardless, no negative structural effects are observed during the simulations. | ||||||||||||||
| c.1997A>C | E666A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive because FoldX is Uncertain while Rosetta is Benign. Overall, the majority of available predictions (six pathogenic vs. five benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -11.122 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.38 | Likely Benign | 0.50 | Likely Benign | 0.407 | Likely Benign | -5.15 | Deleterious | 0.992 | Probably Damaging | 0.863 | Possibly Damaging | 3.45 | Benign | 0.07 | Tolerated | 0.3950 | 0.4878 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2164A>G | S722G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722G is not reported in ClinVar and is present in gnomAD (ID 6‑33441629‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as benign. No evidence from the high‑accuracy tools contradicts the benign predictions, but the consensus and several individual pathogenic predictors suggest a potential deleterious impact. Based on the overall pattern of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and the presence of multiple pathogenic signals. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441629-A-G | 2 | 1.24e-6 | -9.141 | Likely Pathogenic | 0.214 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.1 | 0.67 | Ambiguous | 0.46 | Likely Benign | 0.50 | Likely Benign | 0.270 | Likely Benign | -2.72 | Deleterious | 0.998 | Probably Damaging | 0.863 | Possibly Damaging | 2.49 | Pathogenic | 0.14 | Tolerated | 3.50 | 8 | 0.2202 | 0.3400 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||
| c.2324G>A | R775Q 2D AIThe SynGAP1 missense variant R775Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442482‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the same set of high‑confidence predictors) is “Likely Benign.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | Conflicting | 3 | 6-33442482-G-A | 11 | 1.41e-5 | -4.476 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.63 | Neutral | 0.969 | Probably Damaging | 0.863 | Possibly Damaging | 4.17 | Benign | 0.16 | Tolerated | 3.64 | 6 | 0.2844 | 0.2863 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2834A>T | H945L 2D AIThe SynGAP1 missense variant H945L is reported in gnomAD (ID 6‑33443386‑A‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | 6-33443386-A-T | 2 | 1.24e-6 | -4.741 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.16 | Neutral | 0.948 | Possibly Damaging | 0.863 | Possibly Damaging | 5.05 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.2085 | 0.4526 | -3 | -2 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||
| c.1017G>C | K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic impact for K339N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -11.117 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.0 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.00 | Likely Benign | 0.410 | Likely Benign | -3.88 | Deleterious | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 1.91 | Pathogenic | 0.02 | Affected | 0.3224 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1017G>T | K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact for K339N, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -11.117 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.0 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.00 | Likely Benign | 0.410 | Likely Benign | -3.88 | Deleterious | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 1.91 | Pathogenic | 0.02 | Affected | 0.3224 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.2431C>A | P811T 2D AIThe SynGAP1 missense variant P811T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for P811T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.329 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.94 | Neutral | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 2.77 | Benign | 0.03 | Affected | 0.1679 | 0.6095 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2623G>A | A875T 2D AIThe SynGAP1 missense variant A875T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443175‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | Uncertain | 1 | 6-33443175-G-A | 1 | 6.20e-7 | -3.793 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.56 | Neutral | 0.972 | Probably Damaging | 0.864 | Possibly Damaging | 2.72 | Benign | 0.26 | Tolerated | 3.77 | 5 | 0.1438 | 0.7518 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3302C>A | P1101H 2D AIThe SynGAP1 missense variant P1101H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P1101H, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -5.370 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -1.87 | Neutral | 0.996 | Probably Damaging | 0.864 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 0.2046 | 0.4597 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.103G>T | V35F 2D AIThe SynGAP1 missense variant V35F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for V35F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | -4.114 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.79 | Neutral | 0.923 | Possibly Damaging | 0.865 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.0765 | 0.3421 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2023A>G | N675D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments give AlphaMissense‑Optimized a benign call, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic call, and Foldetta an uncertain result. With an equal split of general predictions but a pathogenic majority in the high‑accuracy consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -12.829 | Likely Pathogenic | 0.497 | Ambiguous | Likely Benign | 1.41 | Ambiguous | 0.4 | -0.26 | Likely Benign | 0.58 | Ambiguous | 1.05 | Destabilizing | 0.246 | Likely Benign | -3.87 | Deleterious | 0.997 | Probably Damaging | 0.865 | Possibly Damaging | 3.53 | Benign | 0.17 | Tolerated | 0.1914 | 0.4901 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.3539T>A | L1180H 2D AIThe SynGAP1 missense variant L1180H is not reported in ClinVar and has no gnomAD allele, so its population frequency is unknown. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments highlight AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus leans benign; Foldetta results are not available. Overall, five of nine individual predictors favor pathogenicity, four favor benign, and the consensus tool suggests benign. Thus, the variant is most likely pathogenic based on the preponderance of high‑confidence predictions, and this assessment is not contradicted by ClinVar, which contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.559845 | Binding | 0.591 | 0.672 | 0.250 | -5.621 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.213 | Likely Benign | -0.22 | Neutral | 0.987 | Probably Damaging | 0.865 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.0991 | 0.0860 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||
| c.3425C>G | S1142C 2D AIThe SynGAP1 missense variant S1142C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign based on the collective evidence, and this conclusion does not conflict with any ClinVar annotation because no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -7.355 | In-Between | 0.182 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.89 | Deleterious | 0.992 | Probably Damaging | 0.866 | Possibly Damaging | 2.70 | Benign | 0.00 | Affected | 0.1170 | 0.6016 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
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