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.995A>C | D332A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D332A 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 and Rosetta, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion 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 | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -12.290 | Likely Pathogenic | 0.876 | Likely Pathogenic | Ambiguous | 1.19 | Ambiguous | 0.2 | 0.32 | Likely Benign | 0.76 | Ambiguous | 0.54 | Ambiguous | 0.458 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.24 | Pathogenic | 0.02 | Affected | 0.2998 | 0.4176 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.997A>G | K333E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K333E 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 SIFT. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact for K333E. 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 | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -14.059 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.30 | Likely Benign | 0.12 | Likely Benign | 0.89 | Ambiguous | 0.488 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.91 | Pathogenic | 0.09 | Tolerated | 0.3429 | 0.1039 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.998A>C | K333T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, and SIFT, whereas a larger set—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score—predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) reports a benign effect. Overall, the majority of evidence points to a pathogenic effect for K333T, and this conclusion does not conflict with 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 | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -11.358 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.0 | -0.15 | Likely Benign | 0.18 | Likely Benign | 0.46 | Likely Benign | 0.506 | Likely Pathogenic | -4.82 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.96 | Pathogenic | 0.08 | Tolerated | 0.1839 | 0.3354 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1000A>C | K334Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. 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) as Benign. With seven tools favoring pathogenicity versus five favoring benign, the overall prediction leans toward pathogenic. 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. | Likely Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -8.185 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.09 | Likely Benign | 0.46 | Likely Benign | 0.357 | Likely Benign | -3.67 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.74 | Pathogenic | 0.03 | Affected | 0.4519 | 0.1062 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1002G>C | K334N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334N 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” Separately, the high‑accuracy AlphaMissense‑Optimized tool predicts pathogenicity, the SGM‑Consensus also predicts pathogenicity, while the Foldetta stability assessment predicts a benign effect. Overall, the majority of predictions (8 pathogenic vs. 5 benign) and the high‑accuracy consensus suggest that K334N is most likely pathogenic, 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 Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -9.581 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.1 | -0.25 | Likely Benign | -0.05 | Likely Benign | 0.18 | Likely Benign | 0.249 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.77 | Pathogenic | 0.02 | Affected | 0.3716 | 0.0958 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1002G>T | K334N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334N 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” Separately, the high‑accuracy AlphaMissense‑Optimized tool predicts pathogenicity, the SGM‑Consensus also predicts pathogenicity, while the Foldetta stability assessment predicts a benign effect. Overall, the majority of predictions (8 pathogenic vs. 5 benign) and the high‑accuracy consensus suggest that K334N is most likely pathogenic, 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 Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -9.581 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.1 | -0.25 | Likely Benign | -0.05 | Likely Benign | 0.18 | Likely Benign | 0.249 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.77 | Pathogenic | 0.02 | Affected | 0.3716 | 0.0958 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1006A>C | K336Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K336Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; 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 (combining FoldX‑MD and Rosetta stability outputs) as benign. Because the predictions are evenly split and the high‑accuracy methods give conflicting results, the variant is best classified as of uncertain significance. This assessment does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. 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 | -12.876 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.02 | Likely Benign | 0.0 | -0.17 | Likely Benign | -0.08 | Likely Benign | 0.18 | Likely Benign | 0.211 | Likely Benign | -3.30 | Deleterious | 0.801 | Possibly Damaging | 0.252 | Benign | 1.58 | Pathogenic | 0.02 | Affected | 0.4698 | 0.1514 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1008G>C | K336N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K336N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments further highlight this split: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus also predicts likely pathogenic, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. No prediction or stability result is missing. Overall, the majority of tools and the high‑accuracy methods lean toward pathogenicity, which is consistent with the lack of ClinVar annotation and gnomAD absence. Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status because ClinVar has no entry. 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 | -13.307 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.09 | Likely Benign | 0.20 | Likely Benign | 0.186 | Likely Benign | -4.09 | Deleterious | 0.801 | Possibly Damaging | 0.315 | Benign | 1.59 | Pathogenic | 0.01 | Affected | 0.3710 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1008G>T | K336N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic impact for K336N, 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 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -13.307 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.09 | Likely Benign | 0.20 | Likely Benign | 0.186 | Likely Benign | -4.09 | Deleterious | 0.801 | Possibly Damaging | 0.315 | Benign | 1.59 | Pathogenic | 0.01 | Affected | 0.3710 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1009A>C | K337Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K337Q 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, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), 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 as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of predictions (8 pathogenic vs. 4 benign) indicate that 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 | C2 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -9.944 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.44 | Likely Benign | 0.43 | Likely Benign | 0.305 | Likely Benign | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 0.3672 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1011G>C | K337N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337N 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, premPS, and SIFT. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). 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 (seven pathogenic vs. five benign) and the high‑accuracy consensus lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion 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 | C2 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -13.095 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.12 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.24 | Likely Benign | -0.02 | Likely Benign | 0.280 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.87 | Pathogenic | 0.11 | Tolerated | 0.2945 | 0.1315 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1011G>T | K337N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337N is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With seven tools supporting pathogenicity versus five supporting benign, the overall prediction leans toward pathogenic. No ClinVar entry contradicts this assessment, and the variant is absent from gnomAD, so the pathogenic prediction is not challenged by population data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -13.095 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.12 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.24 | Likely Benign | -0.02 | Likely Benign | 0.280 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.87 | Pathogenic | 0.11 | Tolerated | 0.2945 | 0.1315 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| 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.1013A>G | D338G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D338G missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, premPS, and polyPhen‑2 HumVar. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Because the majority of available predictors (seven versus three) indicate a deleterious impact, the variant is most likely pathogenic, 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 | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -8.875 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 1.33 | Ambiguous | 0.5 | 1.75 | Ambiguous | 1.54 | Ambiguous | 0.15 | Likely Benign | 0.487 | Likely Benign | -5.51 | Deleterious | 0.771 | Possibly Damaging | 0.315 | Benign | 1.69 | Pathogenic | 0.01 | Affected | 0.4014 | 0.5934 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| 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.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.1018G>C | A340P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340P 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, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy predictors—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—each report a benign outcome. No prediction or folding‑stability result is missing or inconclusive; all available evidence points to a benign impact. Consequently, the variant is most likely benign based on the aggregate 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 Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -4.983 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.5 | -0.58 | Ambiguous | -0.13 | Likely Benign | 0.46 | Likely Benign | 0.279 | Likely Benign | -1.48 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 1.91 | Pathogenic | 0.25 | Tolerated | 0.2178 | 0.5468 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1018G>T | A340S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340S is reported in gnomAD (variant ID 6‑33437923‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. 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 | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | 6-33437923-G-T | 1 | 6.20e-7 | -0.705 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.21 | Likely Benign | -0.46 | Likely Benign | 0.083 | Likely Benign | 1.62 | Neutral | 0.007 | Benign | 0.008 | Benign | 1.93 | Pathogenic | 0.51 | Tolerated | 3.42 | 13 | 0.2852 | 0.6309 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||
| c.1019C>G | A340G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340G 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, 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. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -3.763 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.2 | 1.44 | Ambiguous | 1.05 | Ambiguous | 0.50 | Likely Benign | 0.044 | Likely Benign | -0.34 | Neutral | 0.267 | Benign | 0.127 | Benign | 1.92 | Pathogenic | 0.42 | Tolerated | 0.2355 | 0.4470 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1021G>A | G341S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G341S 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, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact for G341S, 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 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -3.206 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.3 | -1.46 | Ambiguous | -0.53 | Ambiguous | -0.67 | Ambiguous | 0.343 | Likely Benign | 0.73 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 0.37 | Pathogenic | 0.72 | Tolerated | 0.2416 | 0.4215 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1022G>C | G341A 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come only from polyPhen‑2 HumDiv and FATHMM. Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains inconclusive. Overall, the preponderance of evidence indicates that G341A 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 | C2 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -3.211 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.4 | -1.23 | Ambiguous | -0.54 | Ambiguous | -0.03 | Likely Benign | 0.239 | Likely Benign | -1.13 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 0.43 | Pathogenic | 0.15 | Tolerated | 0.3562 | 0.3979 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1030G>A | G344S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344S is listed in ClinVar (ID 981240.0) as Pathogenic and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic; the only inconclusive result is premPS, which is marked Uncertain. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | Pathogenic | 5 | -11.254 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 9.02 | Destabilizing | 0.7 | 6.08 | Destabilizing | 7.55 | Destabilizing | 0.98 | Ambiguous | 0.790 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.45 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.2735 | 0.5324 | 1 | 0 | -0.4 | 30.03 | 217.3 | -51.7 | 0.0 | 0.1 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Because Gly344 lacks a proper side chain, it allows the anti-parallel β sheet strand (res. Gly341-Pro349) to have a slight twist. Within a β strand, side chains normally alternate between outward and inward positions, but glycine is an exception as it allows the alternating pattern to skip a residue. Introducing serine or any other residue with a side chain at position 344 prevents this unique skip in the alternating pattern, causing structural strain or likely preventing correct folding altogether. Additionally, Tyr342 shields Gly344 from the solvent, contributing to twist formation in the β sheet and stabilizing the β-strand.In the variant simulations, the side chain of Ser344 assumes the inward position. However, the hydrophobic niche formed by multiple C2 domain residues (e.g., Val365, Val343, Leu327) is not accommodating for its hydroxyl group. The outward position, not seen in the simulations, would be equally disadvantageous due to the presence of hydrophobic residues on that side as well (e.g., Leu345, Tyr342). Serine is also not well-suited for twist formation, as it tends to suppress twisting and bending in β sheets. At this position, the hydroxyl group of Ser344 could also form hydrogen bonds with the backbone atoms of the Gly-rich Ω loop in the C2 domain (e.g., Thr366, Leu367, Gly378; res. Pro364-Pro398), potentially adversely affecting membrane-loop dynamics and ultimately compromising the stability of the SynGAP-membrane association. | |||||||||||||||
| c.1031G>A | G344D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344D 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) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, 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 Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.527 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.53 | Destabilizing | 1.5 | 11.36 | Destabilizing | 12.95 | Destabilizing | 1.13 | Destabilizing | 0.897 | Likely Pathogenic | -6.30 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.49 | Pathogenic | 0.01 | Affected | 0.1572 | 0.1574 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1031G>C | G344A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G344A 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, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the consensus of the majority of predictors indicates 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 | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -10.439 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 5.11 | Destabilizing | 0.4 | 4.23 | Destabilizing | 4.67 | Destabilizing | 0.58 | Ambiguous | 0.873 | Likely Pathogenic | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -0.32 | Pathogenic | 0.10 | Tolerated | 0.3964 | 0.5685 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1039A>T | T347S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, 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. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.104 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 0.3205 | 0.4707 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.103G>C | V35L 2D  AIThe SynGAP1 missense variant V35L is reported in gnomAD (variant ID 6-33423512‑G‑C) 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, 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, including the high‑accuracy tools, points to a benign effect. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | 6-33423512-G-C | 4 | 2.48e-6 | -2.893 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.58 | Neutral | 0.481 | Possibly Damaging | 0.506 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1026 | 0.4025 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.1040C>G | T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, 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. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.054 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 0.3205 | 0.4707 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1045C>G | P349A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, with the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or pathogenicity scores are available. Overall, the majority of evidence points to a pathogenic effect, and this assessment 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. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -8.663 | Likely Pathogenic | 0.202 | Likely Benign | Likely Benign | 1.37 | Ambiguous | 0.0 | 1.68 | Ambiguous | 1.53 | Ambiguous | 0.76 | Ambiguous | 0.257 | Likely Benign | -6.01 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.3789 | 0.5505 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1045C>T | P349S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P349S missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and premPS. 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 pathogenic. Overall, the majority of tools, including the high‑accuracy methods, predict a pathogenic effect. Thus, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | Uncertain | 1 | -7.654 | In-Between | 0.217 | Likely Benign | Likely Benign | 1.92 | Ambiguous | 0.1 | 2.28 | Destabilizing | 2.10 | Destabilizing | 0.87 | Ambiguous | 0.277 | Likely Benign | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.66 | Pathogenic | 0.06 | Tolerated | 3.37 | 25 | 0.3771 | 0.5756 | 1 | -1 | 0.8 | -10.04 | 194.9 | -18.1 | -0.1 | 0.0 | 0.2 | 0.1 | X | X | Potentially Pathogenic | The cyclic pyrrolidine side chain of Pro349, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), allows the strand to end and make a tight turn before a short α helical section within a loop connecting to another β strand (res. Thr359-Pro364). In the variant simulations, the hydroxyl group of Ser349 forms a hydrogen bond with the backbone amide group of Ala351 in the short helical section. Conversely, the backbone amide group of Ser349 (absent in proline) does not form any intra-protein hydrogen bonds. However, the β strand end connects to the α helical section in a more stable and consistent manner compared to the WT. Although the residue swap does not cause major adverse effects on the protein structure in the simulations, it is possible that the tight turn at the β strand end could not be created during folding without the presence of proline. | ||||||||||||||||
| c.1051G>A | A351T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A351T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain predictions come from Rosetta and Foldetta. 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 inconclusive. Overall, the majority of evidence supports a benign impact for A351T, 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 | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.863 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.0 | 0.80 | Ambiguous | 0.51 | Ambiguous | 0.49 | Likely Benign | 0.040 | Likely Benign | -2.42 | Neutral | 0.524 | Possibly Damaging | 0.138 | Benign | 1.71 | Pathogenic | 0.06 | Tolerated | 0.1337 | 0.6713 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1051G>C | A351P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351P 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, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are Foldetta, PROVEAN, SIFT, FATHMM, and Rosetta. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar reporting; thus the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.559 | Likely Benign | 0.147 | Likely Benign | Likely Benign | -0.89 | Ambiguous | 0.2 | 6.19 | Destabilizing | 2.65 | Destabilizing | 0.62 | Ambiguous | 0.051 | Likely Benign | -3.08 | Deleterious | 0.016 | Benign | 0.007 | Benign | 1.67 | Pathogenic | 0.03 | Affected | 0.1862 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1051G>T | A351S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (integrating FoldX‑MD and Rosetta)—all report benign or likely benign. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely benign; this assessment 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 | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.823 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.25 | Likely Benign | 0.27 | Likely Benign | 0.016 | Likely Benign | -1.42 | Neutral | 0.080 | Benign | 0.023 | Benign | 1.88 | Pathogenic | 0.13 | Tolerated | 0.2558 | 0.5334 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1052C>G | A351G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351G missense variant 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, FoldX, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic), and Foldetta is uncertain. Taken together, the majority of available predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, 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. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.983 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.72 | Ambiguous | 0.55 | Ambiguous | 0.041 | Likely Benign | -2.53 | Deleterious | 0.688 | Possibly Damaging | 0.138 | Benign | 1.77 | Pathogenic | 0.04 | Affected | 0.2298 | 0.4737 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1054A>G | T352A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, integrating FoldX‑MD (benign) and Rosetta (uncertain), reports benign stability. Overall, the preponderance of evidence indicates that T352A 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 | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.952 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.0 | 0.50 | Ambiguous | 0.31 | Likely Benign | 0.45 | Likely Benign | 0.032 | Likely Benign | -1.09 | Neutral | 0.031 | Benign | 0.024 | Benign | 1.73 | Pathogenic | 0.29 | Tolerated | 0.4341 | 0.4938 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1054A>T | T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, 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 | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.670 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.09 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.09 | Likely Benign | -0.01 | Likely Benign | 0.098 | Likely Benign | 0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.81 | Pathogenic | 1.00 | Tolerated | 0.3583 | 0.4880 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1055C>G | T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, 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 | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.670 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.09 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.09 | Likely Benign | -0.01 | Likely Benign | 0.104 | Likely Benign | 0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.81 | Pathogenic | 1.00 | Tolerated | 0.3583 | 0.4880 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1060G>A | A354T 2D AIThe SynGAP1 missense variant A354T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign result. No predictions or folding‑stability analyses are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, 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 | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -2.812 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.7 | 0.11 | Likely Benign | 0.24 | Likely Benign | -0.52 | Ambiguous | 0.097 | Likely Benign | 1.72 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.45 | Tolerated | 0.1731 | 0.6496 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1060G>C | A354P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A354P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, SIFT, and FATHMM, while Rosetta and premPS are inconclusive. The high‑accuracy consensus from AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) both indicate a benign outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect for A354P, 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 | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -5.971 | Likely Benign | 0.239 | Likely Benign | Likely Benign | 2.66 | Destabilizing | 0.2 | 1.55 | Ambiguous | 2.11 | Destabilizing | 0.57 | Ambiguous | 0.241 | Likely Benign | -1.66 | Neutral | 0.001 | Benign | 0.002 | Benign | 1.76 | Pathogenic | 0.04 | Affected | 0.2259 | 0.5884 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1060G>T | A354S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence indicates that A354S 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 | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -3.005 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.02 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.15 | Likely Benign | -0.10 | Likely Benign | 0.071 | Likely Benign | 0.28 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.76 | Pathogenic | 0.21 | Tolerated | 0.2829 | 0.5117 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1061C>G | A354G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354G 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, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. Predictions marked uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign impact for A354G, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -4.285 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.0 | 1.24 | Ambiguous | 0.83 | Ambiguous | 0.65 | Ambiguous | 0.037 | Likely Benign | -1.87 | Neutral | 0.146 | Benign | 0.038 | Benign | 1.75 | Pathogenic | 0.05 | Affected | 0.2563 | 0.4777 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1064G>C | G355A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G355A missense change 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX and Foldetta are uncertain and therefore not counted as evidence. 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) and Foldetta is uncertain. Consequently, the overall prediction leans toward a benign effect, 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. | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -5.431 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.88 | Ambiguous | 0.6 | 0.46 | Likely Benign | 0.67 | Ambiguous | 0.49 | Likely Benign | 0.286 | Likely Benign | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.03 | Affected | 0.4111 | 0.5045 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1069C>G | H357D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H357D 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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) resolves to benign, and Foldetta also predicts a benign outcome. No prediction or folding‑stability result is missing or inconclusive. Overall, the majority of evidence points to 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. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -12.013 | Likely Pathogenic | 0.559 | Ambiguous | Likely Benign | -0.23 | Likely Benign | 0.4 | -0.27 | Likely Benign | -0.25 | Likely Benign | 0.48 | Likely Benign | 0.208 | Likely Benign | -1.90 | Neutral | 0.495 | Possibly Damaging | 0.169 | Benign | 4.22 | Benign | 0.08 | Tolerated | 0.2782 | 0.1976 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||
| c.106C>G | H36D 2D AIThe SynGAP1 missense variant H36D 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts 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 also benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence indicates that H36D 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 | 0.637480 | Disordered | 0.433974 | Uncertain | 0.334 | 0.834 | 0.375 | -2.859 | Likely Benign | 0.225 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.06 | Neutral | 0.043 | Benign | 0.033 | Benign | 4.21 | Benign | 0.00 | Affected | 0.2805 | 0.3496 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.1072T>A | F358I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358I 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports an uncertain impact. Overall, the preponderance of evidence points to a pathogenic effect for F358I, 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 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -10.636 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.30 | Ambiguous | 0.95 | Ambiguous | 0.393 | Likely Benign | -4.45 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 4.07 | Benign | 0.13 | Tolerated | 0.2331 | 0.2821 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1075A>G | T359A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359A 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, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. 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. | Likely Benign | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | -2.948 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.41 | Likely Benign | 0.45 | Likely Benign | 0.103 | Likely Benign | -0.73 | Neutral | 0.000 | Benign | 0.001 | Benign | 1.79 | Pathogenic | 0.34 | Tolerated | 0.4215 | 0.4713 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1075A>T | T359S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T359S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome, while FoldX, Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also favors benign. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. 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 | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | -4.624 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | 0.73 | Ambiguous | 0.62 | Ambiguous | 0.66 | Ambiguous | 0.100 | Likely Benign | -1.87 | Neutral | 0.146 | Benign | 0.024 | Benign | 1.76 | Pathogenic | 0.27 | Tolerated | 0.3637 | 0.4996 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1078G>A | E360K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360K is reported in gnomAD (variant ID 6-33437983‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to FoldX, which scores the variant as benign. In contrast, the majority of algorithms predict a pathogenic impact: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Tools with inconclusive results (Foldetta and premPS) are noted as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, while Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect for E360K. 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 | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | 6-33437983-G-A | -16.006 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.0 | 2.21 | Destabilizing | 1.24 | Ambiguous | 0.55 | Ambiguous | 0.526 | Likely Pathogenic | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 1.68 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.3106 | 0.8594 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||
| c.1081C>A | Q361K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated, 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) and FATHMM predict a pathogenic outcome. High‑accuracy tools that integrate structural and evolutionary information—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all return benign predictions. 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 annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -5.147 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.0 | 0.36 | Likely Benign | 0.27 | Likely Benign | -0.44 | Likely Benign | 0.217 | Likely Benign | 1.29 | Neutral | 0.969 | Probably Damaging | 0.930 | Probably Damaging | 1.73 | Pathogenic | 1.00 | Tolerated | 0.1739 | 0.4701 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1082A>G | Q361R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q361R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, SIFT, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus itself is benign; and Foldetta, which integrates FoldX‑MD (Uncertain) and Rosetta (Benign), yields a benign prediction. Overall, the consensus of available computational evidence indicates that the variant is most likely benign, 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 | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -6.898 | Likely Benign | 0.289 | Likely Benign | Likely Benign | -0.88 | Ambiguous | 0.0 | -0.07 | Likely Benign | -0.48 | Likely Benign | -0.20 | Likely Benign | 0.296 | Likely Benign | -0.56 | Neutral | 0.987 | Probably Damaging | 0.953 | Probably Damaging | 1.71 | Pathogenic | 0.41 | Tolerated | 0.1321 | 0.2955 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1090C>G | P364A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P364A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Stability‑based methods (FoldX, Rosetta, premPS) give uncertain outcomes, and Foldetta is unavailable. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, does not provide a definitive result. Overall, the predictions are discordant; the majority of tools lean toward pathogenicity, but a substantial subset suggests benign. Based on the predictions, the variant is most likely pathogenic, and this does not contradict ClinVar status because there is no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -8.077 | Likely Pathogenic | 0.135 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.0 | 0.69 | Ambiguous | 0.74 | Ambiguous | 0.60 | Ambiguous | 0.320 | Likely Benign | -6.10 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.56 | Pathogenic | 0.06 | Tolerated | 0.3496 | 0.5186 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1093G>C | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity; only FoldX and Rosetta report uncertain stability changes, which are treated as unavailable 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, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect on protein folding stability. Based on the collective predictions, 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. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||
| c.1093G>T | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is catalogued in gnomAD (ID 6‑33437998‑G‑T) but has no ClinVar entry. Across the available in‑silico predictors, the majority (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classify the change as benign; only FoldX and Rosetta report uncertain stability effects, which are treated as unavailable evidence. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from the unanimous benign vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Consequently, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | 6-33437998-G-T | 5 | 3.31e-6 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||
| c.1096A>G | T366A 2D AIThe SynGAP1 missense variant T366A is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and Foldetta provides no definitive stability change. Overall, the computational evidence overwhelmingly favors a benign classification, and this is consistent with the absence of any ClinVar assertion. Therefore, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.983 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.5 | 0.86 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | 0.046 | Likely Benign | -0.94 | Neutral | 0.031 | Benign | 0.016 | Benign | 1.73 | Pathogenic | 0.45 | Tolerated | 0.4141 | 0.4785 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1096A>T | T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta 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 as uncertain. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.273 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.53 | Ambiguous | 0.27 | Likely Benign | 0.058 | Likely Benign | 0.00 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.73 | Pathogenic | 0.78 | Tolerated | 0.3549 | 0.4878 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1097C>G | T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta 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 as uncertain. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.273 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.53 | Ambiguous | 0.27 | Likely Benign | 0.051 | Likely Benign | 0.00 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.73 | Pathogenic | 0.78 | Tolerated | 0.3549 | 0.4878 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.109T>A | S37T 2D  AIThe SynGAP1 missense variant S37T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 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 | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -3.854 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.60 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 0.2093 | 0.5974 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.109T>G | S37A 2D  AIThe SynGAP1 missense variant S37A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion 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 Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -4.052 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.86 | Neutral | 0.140 | Benign | 0.355 | Benign | 3.98 | Benign | 0.00 | Affected | 0.5089 | 0.4970 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.10T>A | S4T 2D AIThe SynGAP1 missense variant S4T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all of which are benign, and therefore SGM‑Consensus also predicts benign. 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 preponderance of evidence from both general and high‑accuracy tools indicates that 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.598 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.01 | Neutral | 0.140 | Benign | 0.153 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1383 | 0.6572 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.10T>C | S4P 2D AIThe SynGAP1 missense variant S4P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, 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, two tools—polyPhen‑2 HumDiv and SIFT—predict a pathogenic impact. High‑accuracy methods give a consistent benign signal: 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 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.131 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.33 | Neutral | 0.676 | Possibly Damaging | 0.307 | Benign | 4.12 | Benign | 0.00 | Affected | 0.2043 | 0.6112 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.10T>G | S4A 2D AIThe SynGAP1 missense variant S4A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates 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 S4A, 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.245 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.02 | Neutral | 0.140 | Benign | 0.097 | Benign | 4.22 | Benign | 0.00 | Affected | 0.4871 | 0.5755 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.1102C>G | P368A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P368A 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, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, 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 (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the balance of evidence leans toward a benign impact for P368A. 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. | C2 | 0.363090 | Structured | 0.439989 | Uncertain | 0.580 | 0.677 | 0.250 | -4.608 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 1.49 | Ambiguous | 0.3 | 1.47 | Ambiguous | 1.48 | Ambiguous | 0.47 | Likely Benign | 0.144 | Likely Benign | -5.42 | Deleterious | 0.767 | Possibly Damaging | 0.344 | Benign | 1.74 | Pathogenic | 0.02 | Affected | 0.3861 | 0.5635 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.1102C>T | P368S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P368S 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and FATHMM. The remaining methods (FoldX, Rosetta, Foldetta, premPS) yield 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 uncertain, so these do not alter the overall interpretation. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status. 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 | -4.790 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 1.68 | Ambiguous | 0.4 | 1.60 | Ambiguous | 1.64 | Ambiguous | 0.52 | Ambiguous | 0.090 | Likely Benign | -5.12 | Deleterious | 0.384 | Benign | 0.113 | Benign | 1.80 | Pathogenic | 0.10 | Tolerated | 0.3700 | 0.5635 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.1105A>G | T369A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369A 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. 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 is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that T369A 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 | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -1.957 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.1 | 1.18 | Ambiguous | 0.64 | Ambiguous | 0.26 | Likely Benign | 0.090 | Likely Benign | -1.93 | Neutral | 0.012 | Benign | 0.016 | Benign | 1.72 | Pathogenic | 0.30 | Tolerated | 0.4538 | 0.5053 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1105A>T | T369S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369S 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No predictions or stability results are missing or inconclusive. Based on the collective 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 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -2.018 | Likely Benign | 0.071 | Likely Benign | Likely Benign | -0.07 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.14 | Likely Benign | 0.18 | Likely Benign | 0.097 | Likely Benign | -0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.78 | Pathogenic | 0.39 | Tolerated | 0.3746 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1108G>A | G370S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G370S is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438013‑G‑A). Consensus predictions from standard in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, FATHMM). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; Foldetta remains uncertain. Overall, the preponderance of evidence points to 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. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | Uncertain | 1 | 6-33438013-G-A | 15 | 9.31e-6 | -3.533 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 2.83 | Destabilizing | 2.0 | 1.05 | Ambiguous | 1.94 | Ambiguous | -0.02 | Likely Benign | 0.282 | Likely Benign | 0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.77 | Tolerated | 3.42 | 19 | 0.2664 | 0.5086 | 1 | 0 | -0.4 | 30.03 | 196.6 | -49.6 | 0.9 | 2.2 | -0.1 | 0.4 | Uncertain | Gly370 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 be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn. | ||||||||||||||
| c.1109G>A | G370D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370D 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, Foldetta (a folding‑stability method that integrates FoldX‑MD and Rosetta outputs) predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact, 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. | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -5.332 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 3.64 | Destabilizing | 3.8 | 0.83 | Ambiguous | 2.24 | Destabilizing | 0.30 | Likely Benign | 0.372 | Likely Benign | -0.44 | Neutral | 0.007 | Benign | 0.001 | Benign | 1.32 | Pathogenic | 0.64 | Tolerated | 0.1632 | 0.1494 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||
| c.1109G>C | G370A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from FoldX, Foldetta, and FATHMM, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicating a likely benign outcome, and Foldetta suggesting a pathogenic impact via combined FoldX‑MD and Rosetta stability analysis. Overall, the majority of evidence points to a benign effect, with only a minority of tools predicting pathogenicity. There is no ClinVar entry to contradict this assessment, so 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 | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -3.334 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 1.3 | 1.62 | Ambiguous | 2.03 | Destabilizing | -0.14 | Likely Benign | 0.304 | Likely Benign | 0.54 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.79 | Tolerated | 0.3883 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1111A>G | S371G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371G is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, 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 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -2.073 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.47 | Likely Benign | 0.3 | 0.49 | Likely Benign | 0.48 | Likely Benign | 0.35 | Likely Benign | 0.164 | Likely Benign | -1.32 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.63 | Benign | 0.17 | Tolerated | 0.3192 | 0.5295 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1112G>A | S371N 2D  AIThe SynGAP1 missense variant S371N is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments are consistent: AlphaMissense‑Optimized classifies the variant as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Based on the preponderance of 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 | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -5.950 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.8 | -0.59 | Ambiguous | -0.19 | Likely Benign | 0.25 | Likely Benign | 0.208 | Likely Benign | -0.31 | Neutral | 0.666 | Possibly Damaging | 0.067 | Benign | 4.64 | Benign | 0.27 | Tolerated | 0.2068 | 0.5100 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1112G>C | S371T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, 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 | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -4.512 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.38 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.06 | Likely Benign | 0.05 | Likely Benign | 0.173 | Likely Benign | -0.65 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.64 | Benign | 0.22 | Tolerated | 0.2245 | 0.6462 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1115G>C | G372A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. 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, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a benign impact for G372A, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -5.163 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 1.52 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.55 | Ambiguous | -0.12 | Likely Benign | 0.465 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.03 | Affected | 0.3956 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1118G>C | G373A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373A is not reported in ClinVar and is absent from gnomAD. Functional prediction consensus shows a predominance of benign calls: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict a benign effect. Pathogenic predictions are limited to SIFT and FoldX, while Rosetta and Foldetta yield uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta remains inconclusive. Overall, the majority of evidence indicates that G373A is most likely benign, 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 | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | -5.181 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 0.8 | 0.69 | Ambiguous | 1.57 | Ambiguous | -0.01 | Likely Benign | 0.227 | Likely Benign | -0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.93 | Benign | 0.01 | Affected | 0.4172 | 0.5053 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1120T>A | S374T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain but does not indicate destabilization. Overall, the evidence strongly favors a benign effect for S374T, 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 | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | -5.415 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.60 | Ambiguous | -0.02 | Likely Benign | 0.176 | Likely Benign | -0.47 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.32 | Benign | 0.12 | Tolerated | 0.2212 | 0.6466 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1120T>G | S374A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374A is reported in gnomAD (6‑33438025‑T‑G) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts 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—AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign effect. Based on the collective predictions, 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 | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | 6-33438025-T-G | -4.245 | Likely Benign | 0.082 | Likely Benign | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.41 | Likely Benign | 0.17 | Likely Benign | 0.10 | Likely Benign | 0.122 | Likely Benign | -0.53 | Neutral | 0.012 | Benign | 0.011 | Benign | 5.32 | Benign | 0.04 | Affected | 4.32 | 13 | 0.5091 | 0.5774 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.1124G>C | G375A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect; 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 | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -5.986 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 2.52 | Destabilizing | 1.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | -0.09 | Likely Benign | 0.419 | Likely Benign | -0.61 | Neutral | 0.020 | Benign | 0.008 | Benign | 1.33 | Pathogenic | 0.27 | Tolerated | 0.3991 | 0.5242 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1127G>A | G376D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G376D 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 PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict 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. | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -7.125 | In-Between | 0.569 | Likely Pathogenic | Likely Benign | 3.10 | Destabilizing | 1.1 | -1.08 | Ambiguous | 1.01 | Ambiguous | 0.52 | Ambiguous | 0.572 | Likely Pathogenic | -1.05 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.32 | Pathogenic | 0.09 | Tolerated | 0.1938 | 0.1235 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||
| c.1127G>C | G376A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G376A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX and Rosetta give uncertain results and are not considered evidence for either side. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. 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 | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -6.016 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.3 | -0.84 | Ambiguous | 0.45 | Likely Benign | 0.00 | Likely Benign | 0.392 | Likely Benign | -0.44 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.33 | Pathogenic | 0.03 | Affected | 0.3868 | 0.4465 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1129A>G | M377V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (gnomAD ID 6‑33438034‑A‑G). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, 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 | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | 6-33438034-A-G | -1.507 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.92 | Ambiguous | 0.3 | 1.27 | Ambiguous | 1.10 | Ambiguous | 0.48 | Likely Benign | 0.161 | Likely Benign | -0.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 5.46 | Benign | 0.15 | Tolerated | 4.32 | 12 | 0.4530 | 0.4096 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||
| 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.112C>T | P38S 2D AIThe SynGAP1 missense variant P38S 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 not available. Based on the collective 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 | 0.497853 | Structured | 0.433285 | Uncertain | 0.344 | 0.791 | 0.375 | -2.727 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -2.13 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.3837 | 0.6111 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.1131G>A | M377I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I (ClinVar ID 3803473.0, status = Uncertain) is present in gnomAD (ID = 6‑33438036‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. 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,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the computational evidence strongly favors a benign classification, 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 | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | Uncertain | 1 | 6-33438036-G-A | 1 | 6.23e-7 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | 0.227 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 0.2240 | 0.4133 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||
| c.1131G>C | M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. Overall, the collective evidence points to a benign impact for M377I, 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 | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | 0.227 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 0.2240 | 0.4133 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1131G>T | M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. Overall, the evidence overwhelmingly supports a benign interpretation, 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 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | 0.227 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 0.2240 | 0.4133 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1132G>A | G378S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic, giving a mixed outcome. Because the predictions are evenly split and the high‑accuracy methods are contradictory, the variant’s functional impact is uncertain. Based on the available 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 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -5.331 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 6.75 | Destabilizing | 2.2 | 7.81 | Destabilizing | 7.28 | Destabilizing | 0.12 | Likely Benign | 0.565 | Likely Pathogenic | -0.63 | Neutral | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 1.33 | Pathogenic | 0.08 | Tolerated | 0.3013 | 0.4724 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1133G>C | G378A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a benign likelihood, while Foldetta—combining FoldX‑MD and Rosetta outputs—predicts a pathogenic effect on protein folding stability. Overall, the majority of evidence points toward a benign impact, and this conclusion is consistent with the absence of ClinVar annotation and gnomAD data. 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 | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -6.450 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 5.06 | Destabilizing | 1.3 | 6.00 | Destabilizing | 5.53 | Destabilizing | -0.04 | Likely Benign | 0.497 | Likely Benign | -0.55 | Neutral | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 1.33 | Pathogenic | 0.18 | Tolerated | 0.4062 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1135T>A | S379T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and the Foldetta stability method. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as pathogenic. 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 | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.646 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.6 | 3.96 | Destabilizing | 2.69 | Destabilizing | 0.06 | Likely Benign | 0.230 | Likely Benign | -0.50 | Neutral | 0.462 | Possibly Damaging | 0.084 | Benign | 3.87 | Benign | 0.16 | Tolerated | 0.2293 | 0.6248 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1135T>C | S379P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, Rosetta, and Foldetta; FoldX is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence—including the high‑accuracy benign predictions—suggests 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 | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.007 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 1.10 | Ambiguous | 0.8 | 2.92 | Destabilizing | 2.01 | Destabilizing | 0.17 | Likely Benign | 0.430 | Likely Benign | -0.41 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 3.83 | Benign | 0.10 | Tolerated | 0.3035 | 0.6594 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1135T>G | S379A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379A is reported in gnomAD (variant ID 6‑33438040‑T‑G) but has no entry in ClinVar. All available in‑silico predictors classify the change as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the consensus SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Consequently, 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 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | 6-33438040-T-G | -4.300 | Likely Benign | 0.077 | Likely Benign | Likely Benign | -0.22 | Likely Benign | 0.3 | 1.03 | Ambiguous | 0.41 | Likely Benign | 0.10 | Likely Benign | 0.217 | Likely Benign | -0.50 | Neutral | 0.012 | Benign | 0.002 | Benign | 3.91 | Benign | 0.21 | Tolerated | 4.32 | 11 | 0.5032 | 0.5555 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.1139G>C | G380A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G380A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FoldX predicts a pathogenic outcome, while Rosetta and Foldetta are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta as uncertain. Overall, the overwhelming majority of evidence points to a benign effect, with no conflict with ClinVar status (which has no entry for this variant). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -6.433 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 3.11 | Destabilizing | 1.0 | -0.15 | Likely Benign | 1.48 | Ambiguous | -0.06 | Likely Benign | 0.422 | Likely Benign | -0.53 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.56 | Benign | 0.17 | Tolerated | 0.3915 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1145G>C | G382A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382A 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, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. 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, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of predictions lean toward a benign effect, and this consensus does not contradict any ClinVar status (none available). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -6.323 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 2.90 | Destabilizing | 0.6 | 3.00 | Destabilizing | 2.95 | Destabilizing | -0.03 | Likely Benign | 0.495 | Likely Benign | -0.59 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.12 | Tolerated | 0.4048 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1148G>C | G383A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Thus, the majority of evidence points to a benign impact, with only a minority of high‑accuracy tools suggesting pathogenicity. The variant is most likely benign based on the overall predictions, and this conclusion 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 | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -6.205 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 3.17 | Destabilizing | 1.2 | 3.47 | Destabilizing | 3.32 | Destabilizing | 0.04 | Likely Benign | 0.178 | Likely Benign | -0.64 | Neutral | 0.055 | Benign | 0.037 | Benign | 4.20 | Benign | 0.11 | Tolerated | 0.3880 | 0.4361 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1150G>A | G384S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G384S (gnomAD ID 6-33438055‑G‑A) is listed in ClinVar with an uncertain significance. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. 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 benignity: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX or Rosetta alone is available. Overall, the preponderance of evidence points to 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. | Likely Benign | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | Uncertain | 1 | 6-33438055-G-A | 1 | 6.22e-7 | -5.243 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 1.92 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.79 | Ambiguous | 0.19 | Likely Benign | 0.315 | Likely Benign | -0.67 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 1.33 | Pathogenic | 0.04 | Affected | 4.32 | 2 | 0.2905 | 0.4924 | 1 | 0 | -0.4 | 30.03 | 202.4 | -49.8 | 0.5 | 1.0 | -0.2 | 0.0 | Uncertain | Gly384 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 glycines, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Ser384 is potentially tolerated in the Ω loop, although the hydroxyl group of Ser384 forms various hydrogen bonds with several other loop residues in the variant simulations. 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.1151G>C | G384A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and Rosetta. Predictions from FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. 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 | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -6.927 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 1.81 | Ambiguous | 0.2 | 2.16 | Destabilizing | 1.99 | Ambiguous | 0.04 | Likely Benign | 0.307 | Likely Benign | -0.40 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 0.3986 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1153T>A | S385T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385T 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, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumVar and SIFT 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—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign effect. Consequently, the variant is most likely benign based on the available 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 | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | -5.904 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.35 | Likely Benign | -0.12 | Likely Benign | 0.214 | Likely Benign | -0.31 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.64 | Benign | 0.03 | Affected | 0.2266 | 0.6259 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| 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.1153T>G | S385A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385A is catalogued in gnomAD (variant ID 6‑33438058‑T‑G) but has no entry in ClinVar. All available in silico predictors report a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: 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 outputs) is benign. Consequently, 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 | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | 6-33438058-T-G | -4.412 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.03 | Likely Benign | 0.1 | 0.19 | Likely Benign | 0.11 | Likely Benign | 0.07 | Likely Benign | 0.243 | Likely Benign | -0.28 | Neutral | 0.140 | Benign | 0.355 | Benign | 4.65 | Benign | 0.13 | Tolerated | 4.32 | 3 | 0.4910 | 0.5366 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||
| c.1157G>C | G386A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change G386A has no ClinVar entry and is not reported in gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (SGM‑Consensus, REVEL, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar) and pathogenic (FoldX, polyPhen‑2 HumDiv, SIFT). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign effect for G386A. 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 | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -6.453 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 2.14 | Destabilizing | 0.7 | 1.05 | Ambiguous | 1.60 | Ambiguous | 0.14 | Likely Benign | 0.331 | Likely Benign | -0.55 | Neutral | 0.718 | Possibly Damaging | 0.332 | Benign | 3.93 | Benign | 0.05 | Affected | 0.3815 | 0.4868 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1163G>C | G388A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388A 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. 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 (combining FoldX‑MD and Rosetta stability outputs) as Pathogenic. Overall, the predictions are mixed, but the two most reliable tools (AlphaMissense‑Optimized and SGM‑Consensus) favor a benign interpretation, while Foldetta suggests instability. Based on the available predictions, 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 | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -6.577 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 2.55 | Destabilizing | 1.9 | 3.57 | Destabilizing | 3.06 | Destabilizing | -0.04 | Likely Benign | 0.457 | Likely Benign | -0.57 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 0.3969 | 0.4837 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1165T>A | S389T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389T is not reported in ClinVar and is present in gnomAD (variant ID 6‑33438070‑T‑A). Functional prediction tools that converge on a benign outcome include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 HumVar and SIFT predict a pathogenic effect. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign outcome. Taken together, the majority of evidence supports a benign classification for S389T, and this conclusion is consistent with the absence of a ClinVar pathogenic report. 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-A | -5.403 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.2 | 0.11 | Likely Benign | 0.24 | Likely Benign | -0.04 | Likely Benign | 0.242 | Likely Benign | -0.26 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 5.07 | Benign | 0.03 | Affected | 4.32 | 8 | 0.2317 | 0.6656 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.1165T>G | S389A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389A is reported in gnomAD (ID 6‑33438070‑T‑G) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts 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 confirm this: AlphaMissense‑Optimized is Benign; the SGM‑Consensus is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports Benign. Overall, the preponderance of evidence indicates 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 | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438070-T-G | -4.199 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.01 | Likely Benign | 0.0 | 0.37 | Likely Benign | 0.19 | Likely Benign | 0.03 | Likely Benign | 0.326 | Likely Benign | -0.39 | Neutral | 0.140 | Benign | 0.355 | Benign | 5.08 | Benign | 0.04 | Affected | 4.32 | 8 | 0.5037 | 0.5963 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.1169G>C | G390A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and Rosetta. The high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as pathogenic. FoldX alone is inconclusive. 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 | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -6.768 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 1.96 | Ambiguous | 0.4 | 2.03 | Destabilizing | 2.00 | Destabilizing | 0.02 | Likely Benign | 0.402 | Likely Benign | -0.55 | Neutral | 0.143 | Benign | 0.028 | Benign | 1.33 | Pathogenic | 0.05 | Affected | 0.4130 | 0.5053 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| 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.1172G>A | G391D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G391D 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and Foldetta, return uncertain results. High‑accuracy methods give a benign call from AlphaMissense‑Optimized; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, six tools favor pathogenicity while five favor benignity, with two uncertain. Thus, the variant is most likely pathogenic based on the current 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. | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -4.651 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 2.59 | Destabilizing | 1.1 | 1.26 | Ambiguous | 1.93 | Ambiguous | 0.22 | Likely Benign | 0.562 | Likely Pathogenic | -0.95 | Neutral | 0.999 | Probably Damaging | 0.960 | Probably Damaging | 1.32 | Pathogenic | 0.29 | Tolerated | 0.1900 | 0.1305 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||
| c.1172G>C | G391A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G391A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, and FATHMM. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of a ClinVar pathogenic classification. 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 | -5.712 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 2.02 | Destabilizing | 0.5 | 1.92 | Ambiguous | 1.97 | Ambiguous | 0.11 | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.633 | Possibly Damaging | 0.219 | Benign | 1.33 | Pathogenic | 0.19 | Tolerated | 0.3828 | 0.4870 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1174A>C | K392Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K392Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and polyPhen‑2 HumDiv. 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, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. No prediction or folding stability result is missing or inconclusive. Based on the collective 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 | 0.541878 | Disordered | 0.405672 | Uncertain | 0.319 | 0.702 | 0.750 | -4.243 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.09 | Likely Benign | 0.23 | Likely Benign | 0.525 | Likely Pathogenic | -2.09 | Neutral | 0.652 | Possibly Damaging | 0.161 | Benign | 4.61 | Benign | 0.06 | Tolerated | 0.5612 | 0.2106 | Weaken | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||
| c.1176G>C | K392N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K392N 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of evidence (9 benign vs 3 pathogenic) 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. | C2 | 0.541878 | Disordered | 0.405672 | Uncertain | 0.319 | 0.702 | 0.750 | -4.136 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.24 | Likely Benign | 0.1 | -0.01 | Likely Benign | 0.12 | Likely Benign | 0.20 | Likely Benign | 0.229 | Likely Benign | -2.61 | Deleterious | 0.276 | Benign | 0.083 | Benign | 4.60 | Benign | 0.02 | Affected | 0.4586 | 0.2454 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1176G>T | K392N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K392N 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, 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 is therefore treated as unavailable. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence (nine benign vs. three pathogenic predictions) 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. | C2 | 0.541878 | Disordered | 0.405672 | Uncertain | 0.319 | 0.702 | 0.750 | -4.136 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.24 | Likely Benign | 0.1 | -0.01 | Likely Benign | 0.12 | Likely Benign | 0.20 | Likely Benign | 0.229 | Likely Benign | -2.61 | Deleterious | 0.276 | Benign | 0.083 | Benign | 4.60 | Benign | 0.02 | Affected | 0.4586 | 0.2454 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1177G>A | G393S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, polyPhen‑2 HumDiv, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other tools provide decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect, and this consensus does not conflict with the absence of ClinVar annotation. Therefore, G393S is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -5.207 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 2.43 | Destabilizing | 0.7 | -0.78 | Ambiguous | 0.83 | Ambiguous | 0.24 | Likely Benign | 0.466 | Likely Benign | -1.76 | Neutral | 0.889 | Possibly Damaging | 0.444 | Benign | 1.33 | Pathogenic | 0.07 | Tolerated | 0.3011 | 0.5232 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| 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.1178G>C | G393A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393A 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -4.507 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 1.93 | Ambiguous | 0.5 | -0.68 | Ambiguous | 0.63 | Ambiguous | 0.22 | Likely Benign | 0.381 | Likely Benign | -1.89 | Neutral | 0.176 | Benign | 0.039 | Benign | 1.33 | Pathogenic | 0.08 | Tolerated | 0.4143 | 0.5193 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1180A>C | K394Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394Q 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, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic outcome are SIFT and Rosetta. The remaining tools—Foldetta, premPS, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also leans toward benign, with two benign votes and two uncertain votes. Foldetta’s stability prediction is uncertain and thus not considered. Overall, the majority of reliable predictions indicate a benign effect, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.261 | In-Between | 0.468 | Ambiguous | Likely Benign | 0.15 | Likely Benign | 0.0 | 2.00 | Destabilizing | 1.08 | Ambiguous | 0.64 | Ambiguous | 0.330 | Likely Benign | -2.46 | Neutral | 0.001 | Benign | 0.009 | Benign | 4.61 | Benign | 0.01 | Affected | 0.5365 | 0.2106 | Weaken | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1180A>G | K394E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K394E is not listed in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438085‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Those that predict a pathogenic effect are premPS, PROVEAN, SIFT, and AlphaMissense‑Default. 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 is uncertain. No prediction or folding‑stability result is available that decisively supports either outcome. Overall, the majority of tools (six benign vs four pathogenic) lean toward a benign interpretation, and this assessment does not contradict the absence of a ClinVar classification. 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. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | 6-33438085-A-G | 1 | 6.20e-7 | -6.903 | Likely Benign | 0.896 | Likely Pathogenic | Ambiguous | 0.07 | Likely Benign | 0.1 | 3.71 | Destabilizing | 1.89 | Ambiguous | 1.20 | Destabilizing | 0.446 | Likely Benign | -2.54 | Deleterious | 0.063 | Benign | 0.038 | Benign | 4.61 | Benign | 0.04 | Affected | 3.44 | 14 | 0.4556 | 0.1916 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1182A>C | K394N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394N 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, FATHMM, and polyPhen‑2 HumVar. Those that agree on a pathogenic effect are Rosetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of available predictions lean toward pathogenicity, 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. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.408 | In-Between | 0.861 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 2.02 | Destabilizing | 1.05 | Ambiguous | 0.66 | Ambiguous | 0.299 | Likely Benign | -3.17 | Deleterious | 0.535 | Possibly Damaging | 0.188 | Benign | 4.60 | Benign | 0.01 | Affected | 0.4353 | 0.2654 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1182A>T | K394N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a mixed signal: benign calls come from REVEL, FoldX, FATHMM, and polyPhen‑2 HumVar, while pathogenic calls come from Rosetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, AlphaMissense‑Optimized) return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic; and Foldetta is uncertain. Taken together, the majority of evidence—including the high‑accuracy consensus—points to a pathogenic effect. 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. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.408 | In-Between | 0.861 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 2.02 | Destabilizing | 1.05 | Ambiguous | 0.66 | Ambiguous | 0.299 | Likely Benign | -3.17 | Deleterious | 0.535 | Possibly Damaging | 0.188 | Benign | 4.60 | Benign | 0.01 | Affected | 0.4353 | 0.2654 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1184G>C | G395A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G395A 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX and Rosetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts 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. Consequently, the variant is most likely benign based on the available 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 | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -3.964 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 1.51 | Ambiguous | 0.3 | -0.59 | Ambiguous | 0.46 | Likely Benign | 0.08 | Likely Benign | 0.160 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.24 | Benign | 0.15 | Tolerated | 0.3848 | 0.5047 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1186G>A | G396S 2D AIThe SynGAP1 missense variant G396S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No tool predicts pathogenicity. Consequently, 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 | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.934 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 1.76 | Ambiguous | 1.6 | 1.12 | Ambiguous | 1.44 | Ambiguous | 0.10 | Likely Benign | 0.223 | Likely Benign | -0.99 | Neutral | 0.004 | Benign | 0.003 | Benign | 3.93 | Benign | 0.56 | Tolerated | 0.2668 | 0.4894 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1187G>A | G396D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, whereas only AlphaMissense‑Default predicts a pathogenic outcome. Tools that assess protein stability (FoldX, Rosetta, Foldetta) yield uncertain or inconclusive results. High‑accuracy consensus methods reinforce the benign assessment: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Benign”; AlphaMissense‑Optimized also predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of evidence, the variant is most likely benign, 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 | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -4.148 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.8 | 1.33 | Ambiguous | 1.63 | Ambiguous | 0.17 | Likely Benign | 0.272 | Likely Benign | -1.49 | Neutral | 0.421 | Benign | 0.080 | Benign | 3.91 | Benign | 0.35 | Tolerated | 0.1702 | 0.1122 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1187G>C | G396A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Consequently, the variant is most likely benign based on the available predictions, 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 | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.655 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.7 | 1.90 | Ambiguous | 1.82 | Ambiguous | 0.41 | Likely Benign | 0.274 | Likely Benign | -1.28 | Neutral | 0.062 | Benign | 0.024 | Benign | 3.93 | Benign | 0.84 | Tolerated | 0.3846 | 0.5255 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.118G>C | D40H 2D AIThe SynGAP1 missense variant D40H is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the consensus of available predictions 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 | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -4.108 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -1.28 | Neutral | 0.172 | Benign | 0.248 | Benign | 3.99 | Benign | 0.00 | Affected | 0.3123 | 0.9007 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.1192C>T | P398S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P398S 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 polyPhen‑2 (HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and SIFT. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give 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 definitive predictions lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, 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. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -6.757 | Likely Benign | 0.490 | Ambiguous | Likely Benign | 1.86 | Ambiguous | 0.3 | 1.78 | Ambiguous | 1.82 | Ambiguous | 0.85 | Ambiguous | 0.544 | Likely Pathogenic | -5.58 | Deleterious | 0.478 | Possibly Damaging | 0.130 | Benign | 5.68 | Benign | 0.03 | Affected | 0.3619 | 0.5737 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.1195G>A | A399T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399T is listed in ClinVar (ID 1990638.0) as Benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. 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 Uncertain. Overall, the variant is most likely benign, and this conclusion aligns with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | Benign | 1 | -5.236 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 0.1 | 0.91 | Ambiguous | 1.08 | Ambiguous | 0.49 | Likely Benign | 0.272 | Likely Benign | -0.40 | Neutral | 0.131 | Benign | 0.039 | Benign | 5.41 | Benign | 0.69 | Tolerated | 3.38 | 26 | 0.1335 | 0.6477 | 1 | 0 | -2.5 | 30.03 | 211.4 | -41.4 | 0.0 | 0.0 | 0.6 | 0.4 | X | Potentially Pathogenic | The methyl group of Ala399, located in an anti-parallel β sheet strand (res. Ala399-Ile411), is swapped for a hydroxyl-containing threonine. In the variant simulations, the hydroxyl group of Thr399 can form H-bonds with the backbone atoms of the residues in the membrane-facing loops (e.g., Gly382) in the C2 domain. Consequently, the ability of the Thr399 side chain to form H-bonds with the membrane-facing loops could adversely affect the dynamics and stability of the SynGAP-membrane association. However, since the effects on the dynamics of the membrane-facing loops can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||
| c.1195G>C | A399P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A399P missense variant 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 polyPhen‑2 HumVar; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic effect. Overall, the majority of evidence points toward a deleterious impact. The variant is most likely pathogenic based on the available predictions, 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. | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -8.809 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 2.29 | Destabilizing | 0.1 | 4.00 | Destabilizing | 3.15 | Destabilizing | 0.74 | Ambiguous | 0.498 | Likely Benign | -1.82 | Neutral | 0.596 | Possibly Damaging | 0.188 | Benign | 5.56 | Benign | 0.10 | Tolerated | 0.1847 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1195G>T | A399S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect, while FoldX, Rosetta, and Foldetta are inconclusive. Grouping by agreement, all available predictors fall into the benign category; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, whereas Foldetta’s stability analysis remains uncertain. 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 | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -4.256 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.89 | Ambiguous | -0.33 | Likely Benign | 0.161 | Likely Benign | 0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.65 | Benign | 0.86 | Tolerated | 0.2494 | 0.4897 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1196C>G | A399G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399G is not reported in ClinVar and is absent from gnomAD. Across a panel of in silico predictors, all available pathogenicity scores classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. Uncertain results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -6.513 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 1.03 | Ambiguous | 0.1 | 1.77 | Ambiguous | 1.40 | Ambiguous | 0.74 | Ambiguous | 0.153 | Likely Benign | -1.59 | Neutral | 0.062 | Benign | 0.024 | Benign | 5.39 | Benign | 0.13 | Tolerated | 0.2174 | 0.4532 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1198G>A | V400M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V400M is reported in gnomAD (ID 6‑33438103‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, only three tools—polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX or premPS is available. Overall, the preponderance of predictions, including the high‑accuracy methods, supports a benign classification, which is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | 6-33438103-G-A | 3 | 1.86e-6 | -5.438 | Likely Benign | 0.573 | Likely Pathogenic | Likely Benign | -1.12 | Ambiguous | 0.1 | -0.16 | Likely Benign | -0.64 | Ambiguous | 0.55 | Ambiguous | 0.443 | Likely Benign | -1.44 | Neutral | 0.868 | Possibly Damaging | 0.289 | Benign | 5.26 | Benign | 0.01 | Affected | 3.38 | 27 | 0.0851 | 0.4643 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||
| c.119A>G | D40G 2D AIThe SynGAP1 D40G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 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 | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -2.777 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.43 | Neutral | 0.012 | Benign | 0.032 | Benign | 4.01 | Benign | 0.00 | Affected | 0.4110 | 0.7949 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1202G>A | R401Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438107‑G‑A). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta’s stability assessment is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | Uncertain | 1 | 6-33438107-G-A | -11.213 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.1 | 1.50 | Ambiguous | 1.23 | Ambiguous | 1.20 | Destabilizing | 0.780 | Likely Pathogenic | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.978 | Probably Damaging | 5.47 | Benign | 0.04 | Affected | 3.38 | 27 | 0.3234 | 0.2269 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.1207A>C | K403Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403Q 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 FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. The premPS assessment is uncertain and does not influence the overall consensus. High‑accuracy analyses show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -12.479 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.36 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.32 | Likely Benign | 0.70 | Ambiguous | 0.376 | Likely Benign | -3.59 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.76 | Benign | 0.01 | Affected | 0.4405 | 0.1954 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1209A>C | K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N 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 of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. 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 (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that 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 | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -10.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.1 | 0.41 | Likely Benign | 1.14 | Ambiguous | 0.74 | Ambiguous | 0.201 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.73 | Benign | 0.05 | Affected | 0.3374 | 0.2492 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1209A>T | K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N 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 of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. 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 (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that 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 | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -10.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.1 | 0.41 | Likely Benign | 1.14 | Ambiguous | 0.74 | Ambiguous | 0.201 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.73 | Benign | 0.05 | Affected | 0.3374 | 0.2492 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1210G>A | A404T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FoldX and premPS are inconclusive, so they are treated as unavailable. High‑accuracy methods corroborate this: 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 benign. Overall, the evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -6.674 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.74 | Ambiguous | 0.1 | -0.01 | Likely Benign | 0.37 | Likely Benign | 0.56 | Ambiguous | 0.060 | Likely Benign | -1.74 | Neutral | 0.049 | Benign | 0.011 | Benign | 4.12 | Benign | 0.09 | Tolerated | 0.1710 | 0.7367 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1210G>C | A404P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A404P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, both polyPhen‑2 versions, and FATHMM, while pathogenic calls arise from FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with 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 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -11.819 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 0.1 | 0.24 | Likely Benign | 1.64 | Ambiguous | 1.17 | Destabilizing | 0.227 | Likely Benign | -3.16 | Deleterious | 0.433 | Benign | 0.080 | Benign | 4.02 | Benign | 0.03 | Affected | 0.2271 | 0.6366 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1210G>T | A404S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. No inconclusive or missing predictions are present. Based on the unanimous benign predictions and the lack of ClinVar evidence, 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 | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -1.937 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.83 | Ambiguous | 0.48 | Likely Benign | 0.28 | Likely Benign | 0.078 | Likely Benign | -0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.22 | Tolerated | 0.2970 | 0.6178 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1211C>G | A404G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS and SIFT. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results and are treated as unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points to a benign impact for A404G, 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 Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -5.277 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.92 | Ambiguous | 0.0 | 1.88 | Ambiguous | 1.40 | Ambiguous | 1.18 | Destabilizing | 0.099 | Likely Benign | -2.34 | Neutral | 0.045 | Benign | 0.013 | Benign | 4.03 | Benign | 0.00 | Affected | 0.2370 | 0.5054 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| 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.1220A>G | Q407R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; premPS is uncertain. 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. With two of the three high‑accuracy methods indicating benign and the remaining one pathogenic, the overall evidence leans toward a benign classification. This conclusion does not contradict ClinVar status, which is currently unreported. 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 | -13.263 | Likely Pathogenic | 0.693 | Likely Pathogenic | Likely Benign | 0.15 | Likely Benign | 0.2 | 0.09 | Likely Benign | 0.12 | Likely Benign | 0.65 | Ambiguous | 0.340 | Likely Benign | -3.52 | Deleterious | 0.909 | Possibly Damaging | 0.889 | Possibly Damaging | 4.02 | Benign | 0.17 | Tolerated | 0.1347 | 0.1596 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1222A>G | T408A 2D AISynGAP1 missense variant T408A is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. The high‑accuracy AlphaMissense‑Optimized score is benign, while 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, also predicts benign. Overall, the balance of evidence favors 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. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | Uncertain | 1 | -8.304 | Likely Pathogenic | 0.114 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.6 | -0.06 | Likely Benign | 0.16 | Likely Benign | 0.72 | Ambiguous | 0.118 | Likely Benign | -3.07 | Deleterious | 0.540 | Possibly Damaging | 0.131 | Benign | 4.16 | Benign | 0.14 | Tolerated | 0.3970 | 0.4674 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||
| c.1222A>T | T408S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408S is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, FoldX, Rosetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Consequently, the variant is most likely benign, and this prediction does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -6.277 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.39 | Likely Benign | 0.25 | Likely Benign | 0.18 | Likely Benign | 0.044 | Likely Benign | -1.48 | Neutral | 0.182 | Benign | 0.127 | Benign | 4.24 | Benign | 0.21 | Tolerated | 0.3256 | 0.4767 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1228A>G | S410G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give 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 evidence points to a benign impact. 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. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -7.147 | In-Between | 0.137 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.1 | 1.33 | Ambiguous | 0.96 | Ambiguous | 0.85 | Ambiguous | 0.117 | Likely Benign | -2.54 | Deleterious | 0.952 | Possibly Damaging | 0.145 | Benign | 4.13 | Benign | 0.19 | Tolerated | 0.2651 | 0.5143 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||
| c.1229G>A | S410N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410N is predicted to be benign by all evaluated in‑silico tools. Consensus predictors (REVEL, SIFT, polyPhen‑2 HumDiv/HumVar, PROVEAN, premPS, FoldX, Rosetta, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly report a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies it as “Likely Benign.” High‑accuracy assessments likewise support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a benign effect. ClinVar contains no entry for this variant, and it is not present in gnomAD. Based on the collective predictions, 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 | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -2.901 | Likely Benign | 0.111 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.16 | Likely Benign | -0.16 | Likely Benign | 0.38 | Likely Benign | 0.049 | Likely Benign | -0.91 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.18 | Tolerated | 0.1310 | 0.5471 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.1229G>C | S410T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Foldetta, SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and premPS. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments are consistent: 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. **Thus, 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 | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -6.559 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.32 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.42 | Likely Benign | 0.00 | Likely Benign | 0.066 | Likely Benign | -0.78 | Neutral | 0.080 | Benign | 0.026 | Benign | 4.24 | Benign | 0.84 | Tolerated | 0.1371 | 0.7159 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1231A>T | I411F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411F 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, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: 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 prediction is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant 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 | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -13.377 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 5.71 | Destabilizing | 0.1 | 4.53 | Destabilizing | 5.12 | Destabilizing | 0.73 | Ambiguous | 0.503 | Likely Pathogenic | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 0.0538 | 0.2853 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1237C>G | P413A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P413A 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 algorithms—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for P413A, 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 | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.686 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.38 | Destabilizing | 0.0 | 0.79 | Ambiguous | 1.59 | Ambiguous | 0.81 | Ambiguous | 0.392 | Likely Benign | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.19 | Benign | 0.02 | Affected | 0.3350 | 0.3863 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1237C>T | P413S 2D 3DClick to see structure in 3D Viewer AISynGAP1 P413S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate a pathogenic effect. High‑accuracy methods give a consistent pathogenic verdict: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) predicts pathogenic; FoldX alone supports pathogenicity while Rosetta remains uncertain. Taken together, the overwhelming majority of predictions support a pathogenic classification, and this is not contradicted by the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.586 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.1 | 1.72 | Ambiguous | 2.39 | Destabilizing | 0.93 | Ambiguous | 0.509 | Likely Pathogenic | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.04 | Affected | 0.3454 | 0.3819 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| 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.1252A>C | K418Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K418Q 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 REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), 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 is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -11.404 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.10 | Likely Benign | 0.1 | 0.17 | Likely Benign | 0.14 | Likely Benign | 0.30 | Likely Benign | 0.263 | Likely Benign | -3.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.55 | Benign | 0.13 | Tolerated | 0.4105 | 0.0696 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1254A>C | K418N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that K418N 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 | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -13.310 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.57 | Ambiguous | 0.0 | 0.77 | Ambiguous | 0.67 | Ambiguous | 0.56 | Ambiguous | 0.132 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.3483 | 0.0606 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1254A>T | K418N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions are provided by REVEL and FATHMM, whereas pathogenic predictions are given by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors classify K418N as pathogenic, 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 | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -13.310 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.57 | Ambiguous | 0.0 | 0.77 | Ambiguous | 0.67 | Ambiguous | 0.56 | Ambiguous | 0.132 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.3483 | 0.0606 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1258T>A | F420I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, 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 | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.567 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.0 | 3.64 | Destabilizing | 3.26 | Destabilizing | 1.25 | Destabilizing | 0.330 | Likely Benign | -5.46 | Deleterious | 0.575 | Possibly Damaging | 0.059 | Benign | 3.22 | Benign | 0.02 | Affected | 0.1864 | 0.2113 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1261G>C | A421P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL, FATHMM, and polyPhen‑2 HumVar, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, 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 confirm this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a pathogenic effect. Taken together, the overwhelming majority of evidence points to a pathogenic impact for A421P, 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 | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -13.126 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.51 | Destabilizing | 0.2 | 8.77 | Destabilizing | 6.64 | Destabilizing | 1.17 | Destabilizing | 0.371 | Likely Benign | -4.31 | Deleterious | 0.855 | Possibly Damaging | 0.420 | Benign | 3.39 | Benign | 0.04 | Affected | 0.1963 | 0.3343 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1261G>T | A421S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus predicts pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns with the SGM‑Consensus result; there is 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 Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -9.220 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.89 | Ambiguous | 0.70 | Ambiguous | 0.155 | Likely Benign | -2.50 | Deleterious | 0.058 | Benign | 0.072 | Benign | 3.46 | Benign | 0.08 | Tolerated | 0.2247 | 0.3621 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1262C>G | A421G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A421G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of tools and the SGM Consensus favor a pathogenic interpretation, while a minority suggest benign. Because there is no ClinVar entry, the predictions do not contradict existing clinical classification. The variant is most likely pathogenic based on the collective computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -9.699 | Likely Pathogenic | 0.757 | Likely Pathogenic | Likely Benign | 1.47 | Ambiguous | 0.1 | 2.13 | Destabilizing | 1.80 | Ambiguous | 1.19 | Destabilizing | 0.137 | Likely Benign | -3.59 | Deleterious | 0.536 | Possibly Damaging | 0.176 | Benign | 3.41 | Benign | 0.05 | Affected | 0.1692 | 0.2499 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1273A>G | T425A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Two tools (premPS and AlphaMissense‑Optimized) give uncertain results and are treated as unavailable. High‑accuracy assessments show SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as uncertain. Overall, the balance of evidence leans toward pathogenicity, 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 | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -8.945 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | -0.31 | Likely Benign | 0.1 | -0.05 | Likely Benign | -0.18 | Likely Benign | 0.70 | Ambiguous | 0.372 | Likely Benign | -4.17 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.42 | Benign | 0.09 | Tolerated | 0.2971 | 0.2572 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1273A>T | T425S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425S 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, Rosetta) 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 majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -7.420 | In-Between | 0.676 | Likely Pathogenic | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.50 | Ambiguous | 0.63 | Ambiguous | 0.275 | Likely Benign | -3.05 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.2511 | 0.2324 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1274C>G | T425S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425S 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, Rosetta) 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 majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -7.420 | In-Between | 0.676 | Likely Pathogenic | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.50 | Ambiguous | 0.63 | Ambiguous | 0.184 | Likely Benign | -3.05 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.2511 | 0.2324 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1277A>G | N426S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and the Foldetta stability assessment is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the majority of predictions support a benign impact, and this 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 | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -5.215 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.67 | Ambiguous | 0.03 | Likely Benign | 0.131 | Likely Benign | -2.37 | Neutral | 0.998 | Probably Damaging | 0.921 | Probably Damaging | 3.47 | Benign | 0.33 | Tolerated | 0.2224 | 0.3188 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1278C>A | N426K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426K resides 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 include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.659 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 0.00 | Likely Benign | 0.02 | Likely Benign | 0.54 | Ambiguous | 0.197 | Likely Benign | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.978 | Probably Damaging | 3.38 | Benign | 0.12 | Tolerated | 0.1906 | 0.2822 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1278C>G | N426K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N426K is located in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect on protein stability. Overall, the majority of predictions lean toward pathogenicity, with a split in the most reliable methods. Therefore, the variant is most likely pathogenic based on the current computational evidence, 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 | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.659 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 0.00 | Likely Benign | 0.02 | Likely Benign | 0.54 | Ambiguous | 0.197 | Likely Benign | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.978 | Probably Damaging | 3.38 | Benign | 0.12 | Tolerated | 0.1906 | 0.2822 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1279C>G | H427D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H427D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from the available tools suggests pathogenicity, and the absence of a ClinVar classification means there is no contradiction. Therefore, based on the current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -3.684 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.76 | Ambiguous | 0.1 | 1.26 | Ambiguous | 1.01 | Ambiguous | 0.10 | Likely Benign | 0.163 | Likely Benign | -1.43 | Neutral | 0.677 | Possibly Damaging | 0.236 | Benign | 3.58 | Benign | 0.12 | Tolerated | 0.2241 | 0.1678 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.127G>A | G43S 2D AIThe SynGAP1 missense variant G43S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33423536‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same four high‑accuracy tools) also as benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, 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 | 0.308712 | Structured | 0.431462 | Uncertain | 0.396 | 0.762 | 0.375 | Uncertain | 2 | 6-33423536-G-A | 1 | 6.20e-7 | -3.301 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.30 | Neutral | 0.162 | Benign | 0.096 | Benign | 4.29 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2559 | 0.4064 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.1286G>A | R429Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438191‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while premPS is inconclusive. The high‑accuracy consensus (SGM Consensus) – a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – yields a “Likely Benign” result. AlphaMissense‑Optimized itself predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Taken together, the preponderance of evidence points to a benign impact for R429Q, 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 | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | Uncertain | 2 | 6-33438191-G-A | 10 | 6.20e-6 | -8.227 | Likely Pathogenic | 0.143 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.41 | Likely Benign | 0.98 | Ambiguous | 0.156 | Likely Benign | -1.25 | Neutral | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.47 | Benign | 0.58 | Tolerated | 3.38 | 25 | 0.2518 | 0.1985 | 1 | 1 | 1.0 | -28.06 | 235.8 | 59.5 | 0.0 | 0.0 | -0.3 | 0.4 | X | Potentially Pathogenic | The guanidinium group of the Arg429 side chain, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or an H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, Gln429 cannot form ionic interactions with the acidic residues; however, the carboxamide group can form multiple H-bonds. The H-bonding coordination of the Asn429 side chain varied between the replica simulations. In one simulation, three H-bonds were formed simultaneously with the Asp467 side chain, the backbone carbonyl group of Asn426, and the amide group of Met430 at the end of the same α helix. The residue swap could affect the tertiary structure assembly during folding due to weaker bond formation, but no large-scale negative effects were seen during the simulations. | |||||||||||||
| c.128G>A | G43D 2D AIThe SynGAP1 missense variant G43D 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 consistent with the lack of any ClinVar pathogenic classification. 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 | -5.867 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.84 | Neutral | 0.870 | Possibly Damaging | 0.500 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 0.2018 | 0.2339 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1290G>A | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is catalogued in gnomAD (6‑33438195‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. 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 | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | 6-33438195-G-A | 1 | 6.19e-7 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | 0.068 | Likely Benign | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.1524 | 0.4116 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||
| c.1290G>C | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. 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, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors is that M430I 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 | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | 0.068 | Likely Benign | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.1524 | 0.4116 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1290G>T | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s combined FoldX‑MD/Rosetta output is unavailable due to the uncertain FoldX result. Overall, the evidence overwhelmingly supports a benign classification for M430I, 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 | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | 0.068 | Likely Benign | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 0.1524 | 0.4116 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1297G>A | A433T 2D AIThe SynGAP1 A433T 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, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: 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. 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 | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -5.499 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.35 | Likely Benign | 0.5 | -0.02 | Likely Benign | 0.17 | Likely Benign | 0.40 | Likely Benign | 0.088 | Likely Benign | -1.41 | Neutral | 0.964 | Probably Damaging | 0.481 | Possibly Damaging | 3.41 | Benign | 0.08 | Tolerated | 0.0891 | 0.5554 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| 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.1297G>T | A433S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely benign classification; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence points to a benign impact for A433S, 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 | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -3.861 | Likely Benign | 0.077 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | 0.41 | Likely Benign | 0.19 | Likely Benign | -0.21 | Likely Benign | 0.077 | Likely Benign | 0.35 | Neutral | 0.597 | Possibly Damaging | 0.391 | Benign | 3.46 | Benign | 0.28 | Tolerated | 0.1938 | 0.3975 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1298C>G | A433G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that 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 | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -5.044 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.59 | Ambiguous | 0.0 | 1.21 | Ambiguous | 0.90 | Ambiguous | 0.70 | Ambiguous | 0.038 | Likely Benign | -1.54 | Neutral | 0.035 | Benign | 0.014 | Benign | 3.38 | Benign | 0.15 | Tolerated | 0.1629 | 0.2919 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1309C>G | P437A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437A 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, Rosetta, FATHMM, AlphaMissense‑Optimized, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Tools with uncertain or inconclusive results are AlphaMissense‑Default, FoldX, and Foldetta. High‑accuracy assessments give AlphaMissense‑Optimized a benign prediction. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic), yields a pathogenic consensus. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the balance of evidence leans toward a pathogenic effect for P437A, and this conclusion 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. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -12.059 | Likely Pathogenic | 0.392 | Ambiguous | Likely Benign | 1.23 | Ambiguous | 0.0 | -3.14 | Stabilizing | -0.96 | Ambiguous | 0.50 | Likely Benign | 0.266 | Likely Benign | -6.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0.3489 | 0.4775 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.1312G>A | A438T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33438217‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status of “Uncertain.” Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | Conflicting | 3 | 6-33438217-G-A | 16 | 9.91e-6 | -5.339 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.0 | -0.07 | Likely Benign | 0.07 | Likely Benign | 0.36 | Likely Benign | 0.021 | Likely Benign | -0.81 | Neutral | 0.300 | Benign | 0.011 | Benign | 4.18 | Benign | 0.14 | Tolerated | 3.38 | 26 | 0.0999 | 0.5574 | 1 | 0 | -2.5 | 30.03 | 214.2 | -42.7 | -0.3 | 0.1 | -0.4 | 0.1 | X | Potentially Benign | The methyl group of Ala438, located in a four-residue loop connecting two α helices (res. Asn440-Thr458 and Pro413-Glu436), packs against hydrophobic residues from a nearby α helix or loop residues (e.g., Leu703, Val699). In the variant simulations, the methyl group of Thr438 is able to establish similar hydrophobic packing. Moreover, the hydroxyl group also H-bonds with nearby residues, such as the carbonyl group of the neighboring loop residue Pro437. Accordingly, the residue swap does not generate an apparent negative effect on the protein structure based on the simulations. | |||||||||||||
| c.1312G>C | A438P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A438P missense variant 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, whereas those that predict a pathogenic impact are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv), SIFT, and AlphaMissense‑Default; premPS and ESM1b are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, six tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus is split, but the majority of evidence points toward a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, 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. | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -7.955 | In-Between | 0.721 | Likely Pathogenic | Likely Benign | 2.21 | Destabilizing | 0.1 | 6.36 | Destabilizing | 4.29 | Destabilizing | 0.83 | Ambiguous | 0.158 | Likely Benign | -2.46 | Neutral | 0.815 | Possibly Damaging | 0.137 | Benign | 4.09 | Benign | 0.05 | Affected | 0.1624 | 0.4150 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1312G>T | A438S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. The only inconclusive results come from Rosetta and premPS, which are listed as uncertain. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: 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 reports benign. Overall, the evidence strongly supports a benign effect, 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 | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -6.085 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.0 | 0.62 | Ambiguous | 0.46 | Likely Benign | 0.68 | Ambiguous | 0.012 | Likely Benign | -1.27 | Neutral | 0.042 | Benign | 0.035 | Benign | 4.14 | Benign | 0.15 | Tolerated | 0.2143 | 0.3995 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1313C>G | A438G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only PROVEAN predicts a pathogenic outcome. 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. Overall, the majority of evidence points to a benign impact for A438G, 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 | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -5.790 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 1.08 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.43 | Ambiguous | 0.80 | Ambiguous | 0.034 | Likely Benign | -2.51 | Deleterious | 0.247 | Benign | 0.037 | Benign | 4.12 | Benign | 0.11 | Tolerated | 0.1788 | 0.2719 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1319A>G | N440S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or likely benign. Only FoldX and premPS returned uncertain results, which are treated as unavailable. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Consequently, 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 | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -1.753 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.30 | Likely Benign | -0.50 | Ambiguous | 0.104 | Likely Benign | 1.15 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.53 | Benign | 0.92 | Tolerated | 0.2024 | 0.3556 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1320T>A | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K 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, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise 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 is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, 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. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.058 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.1320T>G | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K 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, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise 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 is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, 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. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.057 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.1324A>C | K442Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K442Q 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, 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) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact, 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 | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -10.410 | Likely Pathogenic | 0.562 | Ambiguous | Likely Benign | 0.05 | Likely Benign | 0.1 | 0.03 | Likely Benign | 0.04 | Likely Benign | 0.25 | Likely Benign | 0.268 | Likely Benign | -3.10 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.39 | Benign | 0.18 | Tolerated | 0.3353 | 0.1014 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.1326A>C | K442N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta (which integrates FoldX‑MD and Rosetta outputs). Tools that predict a pathogenic effect 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, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, but the presence of several strong benign predictions and a benign folding‑stability result introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, and this 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 | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.039 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | 0.161 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 0.2686 | 0.1314 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1326A>T | K442N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta (which integrates FoldX‑MD and Rosetta outputs). Tools that predict a pathogenic effect 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, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, but the presence of several strong benign predictions and a benign folding‑stability result introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, and this 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 | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.039 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | 0.161 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 0.2686 | 0.1314 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1327G>A | G443S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. Only Rosetta and premPS yield uncertain results, which are treated as unavailable. Grouping by consensus, the benign‑predicting tools outnumber any pathogenic calls (none). High‑accuracy assessments reinforce this view: 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 reports benign. Therefore, the variant 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 | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -1.258 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.1 | -0.72 | Ambiguous | -0.24 | Likely Benign | -0.65 | Ambiguous | 0.087 | Likely Benign | 0.40 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.51 | Benign | 0.34 | Tolerated | 0.2409 | 0.3416 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1328G>A | G443D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443D 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, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. Uncertain results come from Rosetta and Foldetta. 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 inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. The variant is most likely benign based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -6.818 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.2 | -1.72 | Ambiguous | -0.96 | Ambiguous | 0.32 | Likely Benign | 0.072 | Likely Benign | -0.50 | Neutral | 0.345 | Benign | 0.072 | Benign | 3.63 | Benign | 0.43 | Tolerated | 0.1687 | 0.2090 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1328G>C | G443A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, 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 | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -0.332 | Likely Benign | 0.101 | Likely Benign | Likely Benign | -0.59 | Ambiguous | 0.1 | -1.61 | Ambiguous | -1.10 | Ambiguous | -0.52 | Ambiguous | 0.033 | Likely Benign | -1.04 | Neutral | 0.022 | Benign | 0.011 | Benign | 3.41 | Benign | 0.54 | Tolerated | 0.3539 | 0.3192 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1330A>C | K444Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K444Q 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 premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, 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 further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K444Q, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -12.876 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.34 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.35 | Ambiguous | 1.04 | Destabilizing | 0.382 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 0.4112 | 0.1057 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1332G>C | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta’s stability assessment is uncertain and therefore not used as evidence. Overall, the preponderance of evidence points to a pathogenic effect for K444N. 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 | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | 0.286 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3282 | 0.1213 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1332G>T | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N 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. Tools that predict a pathogenic effect include FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | 0.286 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3282 | 0.1213 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1336G>A | E446K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446K is not reported in ClinVar (ClinVar status: not present) and is found in gnomAD (ID 6‑33438241‑G‑A). Prediction tools that agree on a benign effect include only FATHMM. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy methods give the following: AlphaMissense‑Optimized is uncertain; SGM‑Consensus indicates likely pathogenic; Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic impact. Thus, 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. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | 6-33438241-G-A | 1 | 6.19e-7 | -14.140 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.4 | 1.57 | Ambiguous | 1.19 | Ambiguous | 0.81 | Ambiguous | 0.518 | Likely Pathogenic | -3.75 | Deleterious | 0.994 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 3.38 | 31 | 0.2141 | 0.6511 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| 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.1342G>A | A448T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448T 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 only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. 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 pathogenic. Taken together, the overwhelming majority of evidence indicates that A448T 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 | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.192 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | 0.558 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.1187 | 0.5050 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1342G>C | A448P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). 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 pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among 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 | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | 0.650 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.1758 | 0.3626 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1342G>T | A448S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. 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 predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.213 | Likely Pathogenic | 0.590 | Likely Pathogenic | Likely Benign | 1.18 | Ambiguous | 0.1 | 1.97 | Ambiguous | 1.58 | Ambiguous | 0.55 | Ambiguous | 0.310 | Likely Benign | -2.96 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.27 | Benign | 0.06 | Tolerated | 0.2420 | 0.3471 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1343C>G | A448G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; FoldX is inconclusive. High‑accuracy assessments further clarify the impact: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. 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 because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.984 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | 0.378 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 0.2135 | 0.2936 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1346G>A | S449N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449N is not reported in ClinVar (ClinVar status: not listed) but is present in the gnomAD database (gnomAD ID: 6‑33438251‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS (uncertain) and ESM1b (uncertain). High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. 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 | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | 6-33438251-G-A | 1 | 6.19e-7 | -7.692 | In-Between | 0.210 | Likely Benign | Likely Benign | 0.38 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.81 | Ambiguous | 0.070 | Likely Benign | -2.31 | Neutral | 0.372 | Benign | 0.026 | Benign | 3.37 | Benign | 0.18 | Tolerated | 3.37 | 32 | 0.1085 | 0.3767 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||
| c.1346G>C | S449T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, 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). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on these predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -6.262 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | 0.039 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 0.1219 | 0.5077 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1348G>A | A450T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450T 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give 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. Because the majority of conventional tools lean toward benign and no ClinVar evidence contradicts this, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.149 | Likely Pathogenic | 0.380 | Ambiguous | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.98 | Ambiguous | 0.74 | Ambiguous | 0.81 | Ambiguous | 0.233 | Likely Benign | -3.35 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.0943 | 0.5902 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1348G>C | A450P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450P missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score all classify the change as pathogenic. The high‑accuracy predictors give consistent pathogenic results: 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 predicts pathogenic. premPS remains uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the absence of a benign ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -15.378 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.75 | Destabilizing | 0.3 | 8.32 | Destabilizing | 5.54 | Destabilizing | 0.72 | Ambiguous | 0.459 | Likely Benign | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1494 | 0.4309 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1348G>T | A450S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450S 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining methods—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; 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 balance of evidence (five benign versus four pathogenic predictions, with three uncertain) suggests 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. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.257 | Likely Pathogenic | 0.274 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.0 | 1.35 | Ambiguous | 1.08 | Ambiguous | 0.69 | Ambiguous | 0.268 | Likely Benign | -2.70 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.2003 | 0.4322 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1349C>G | A450G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. The majority of other in silico predictors (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the variant as pathogenic; FoldX is inconclusive. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenic. Overall, the preponderance of evidence indicates that A450G 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 | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -11.090 | Likely Pathogenic | 0.695 | Likely Pathogenic | Likely Benign | 1.79 | Ambiguous | 0.0 | 2.29 | Destabilizing | 2.04 | Destabilizing | 1.23 | Destabilizing | 0.355 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.1670 | 0.3078 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.134A>G | N45S 2D AIThe SynGAP1 missense variant N45S 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, 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 the variant, 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 | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -2.740 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.38 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.3949 | 0.7617 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.1357C>G | H453D 2D 3DClick to see structure in 3D Viewer AISynGAP1 H453D 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 are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce a pathogenic interpretation: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. premPS remains uncertain. Overall, the majority of evidence points to a pathogenic effect for H453D, 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 | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.256 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.0 | 2.68 | Destabilizing | 3.01 | Destabilizing | 0.97 | Ambiguous | 0.443 | Likely Benign | -8.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 0.2225 | 0.1815 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| 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.1360A>T | I454F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454F 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. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. premPS is uncertain and does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -12.468 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 4.15 | Destabilizing | 0.7 | 2.96 | Destabilizing | 3.56 | Destabilizing | 0.70 | Ambiguous | 0.464 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0422 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1366C>A | Q456K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456K is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; premPS and AlphaMissense‑Optimized are 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. Overall, the majority of tools (six pathogenic vs five benign) and the SGM‑Consensus result point toward a pathogenic interpretation, while Foldetta suggests stability‑preserving benignity. Thus, the variant is most likely pathogenic based on current predictions, 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 | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -13.768 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.22 | Likely Benign | 0.78 | Ambiguous | 0.391 | Likely Benign | -3.75 | Deleterious | 0.969 | Probably Damaging | 0.875 | Possibly Damaging | 3.36 | Benign | 0.13 | Tolerated | 0.1321 | 0.2547 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1367A>G | Q456R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta (a folding‑stability method combining FoldX‑MD and Rosetta outputs) predicts benign. No evidence from the data contradicts ClinVar status, which is currently unclassified. Based on the available predictions, the variant is most likely benign, though the evidence is conflicting and does not conflict with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -11.326 | Likely Pathogenic | 0.801 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.17 | Likely Benign | 0.33 | Likely Benign | 0.295 | Likely Benign | -3.69 | Deleterious | 0.980 | Probably Damaging | 0.943 | Probably Damaging | 3.37 | Benign | 0.20 | Tolerated | 0.1241 | 0.1124 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1369A>G | S457G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457G 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: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S457G. 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 | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -9.154 | Likely Pathogenic | 0.811 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.0 | 0.87 | Ambiguous | 0.87 | Ambiguous | 0.65 | Ambiguous | 0.382 | Likely Benign | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.35 | Benign | 0.13 | Tolerated | 0.2735 | 0.4074 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| 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.136C>T | P46S 2D AIThe SynGAP1 missense variant P46S 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 | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | Uncertain | 1 | -3.338 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.60 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.3904 | 0.5771 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||
| 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.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.1372A>G | T458A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458A 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 REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of reliable predictors (six pathogenic vs. five benign) indicate a pathogenic effect. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -10.734 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.34 | Likely Benign | 0.56 | Ambiguous | 0.358 | Likely Benign | -4.27 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 0.4137 | 0.4257 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1372A>T | T458S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458S missense variant has no ClinVar entry and is not present in gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, FoldX, Rosetta, SIFT, and FATHMM; pathogenic calls from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments further split the signal: AlphaMissense‑Optimized remains uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Because the majority of standard predictors are evenly divided and the high‑accuracy methods disagree, the variant’s effect cannot be confidently classified as benign or pathogenic. Thus, the variant is of uncertain significance, and this uncertainty does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -8.465 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.55 | Ambiguous | 0.260 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.48 | Benign | 0.13 | Tolerated | 0.3525 | 0.4349 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1375G>A | G459S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic 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 Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -10.979 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 2.34 | Destabilizing | 0.1 | 0.77 | Ambiguous | 1.56 | Ambiguous | 0.60 | Ambiguous | 0.414 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.09 | Benign | 0.05 | Affected | 0.2340 | 0.5197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1376G>A | G459D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate benign effects include REVEL and FATHMM, while the majority of tools predict pathogenicity: FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, and premPS. 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 evidence points to a pathogenic effect for G459D, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.258 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.1 | 0.56 | Ambiguous | 1.39 | Ambiguous | 0.93 | Ambiguous | 0.454 | Likely Benign | -6.18 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.05 | Affected | 0.1466 | 0.1905 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1376G>C | G459A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G459A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled Uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. 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, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain and therefore not considered evidence. Overall, the majority of reliable tools indicate a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.684 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | 0.469 | Likely Benign | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.3529 | 0.5161 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1378A>C | K460Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K460Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain result from AlphaMissense‑Optimized; Foldetta likewise reports no definitive stability change. 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -9.404 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 0.71 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.86 | Ambiguous | 0.312 | Likely Benign | -3.15 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.14 | Tolerated | 0.4523 | 0.1454 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1380G>C | K460N 2D AIThe SynGAP1 missense variant K460N 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, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and the protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the balance of evidence—six pathogenic versus five benign predictions, a pathogenic SGM Consensus, and a pathogenic AlphaMissense‑Optimized—suggests that K460N is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is not currently catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1380G>T | K460N 2D AIThe SynGAP1 K460N missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the majority of evidence—including the high‑accuracy tools—points to a pathogenic impact for K460N. 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. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1381G>A | A461T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A461T 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, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta is also inconclusive. Overall, the balance of evidence favors a benign classification, 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 | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.885 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 1.21 | Ambiguous | 0.2 | 0.51 | Ambiguous | 0.86 | Ambiguous | 0.65 | Ambiguous | 0.214 | Likely Benign | -3.27 | Deleterious | 0.508 | Possibly Damaging | 0.042 | Benign | 3.40 | Benign | 0.13 | Tolerated | 0.1083 | 0.5930 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| 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.1381G>T | A461S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv), SIFT, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta’s stability analysis is also unavailable. Overall, the balance of evidence leans toward a benign 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. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.663 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.87 | Ambiguous | 0.0 | 1.18 | Ambiguous | 1.03 | Ambiguous | 0.63 | Ambiguous | 0.236 | Likely Benign | -2.74 | Deleterious | 0.600 | Possibly Damaging | 0.289 | Benign | 3.36 | Benign | 0.02 | Affected | 0.2401 | 0.4551 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1382C>G | A461G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461G has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; the remaining tools (FoldX, premPS, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. 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 majority of evidence points toward a pathogenic effect, with no ClinVar record to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -11.360 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 1.46 | Ambiguous | 0.1 | 2.06 | Destabilizing | 1.76 | Ambiguous | 0.83 | Ambiguous | 0.276 | Likely Benign | -3.79 | Deleterious | 0.991 | Probably Damaging | 0.628 | Possibly Damaging | 3.32 | Benign | 0.00 | Affected | 0.1988 | 0.3317 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1384A>C | K462Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K462Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. 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) as benign. Overall, the majority of tools and the protein‑stability analysis favor a benign effect, while the consensus pathogenic score introduces uncertainty. Thus, the variant is most likely benign; this assessment does not contradict ClinVar status, which has no entry for K462Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.144 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 0.12 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.23 | Likely Benign | 0.48 | Likely Benign | 0.384 | Likely Benign | -3.85 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 0.4639 | 0.1286 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| 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.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.1390T>A | F464I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464I 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 limited to FATHMM, while all other evaluated algorithms—including 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 assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 conclusion 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 | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -11.210 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.77 | Destabilizing | 0.2 | 4.35 | Destabilizing | 4.56 | Destabilizing | 1.23 | Destabilizing | 0.539 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1439 | 0.2002 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1396T>A | S466T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466T 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, Foldetta, 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, and FATHMM. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence points to a benign impact. Therefore, 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 | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -5.488 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.2 | -1.02 | Ambiguous | -0.36 | Likely Benign | -0.65 | Ambiguous | 0.414 | Likely Benign | 1.05 | Neutral | 0.740 | Possibly Damaging | 0.872 | Possibly Damaging | -1.51 | Pathogenic | 1.00 | Tolerated | 0.0928 | 0.5152 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1396T>C | S466P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS (Uncertain). High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -13.107 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.2 | 2.83 | Destabilizing | 2.75 | Destabilizing | 0.95 | Ambiguous | 0.811 | Likely Pathogenic | -3.02 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | -1.55 | Pathogenic | 0.04 | Affected | 0.1617 | 0.4915 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1396T>G | S466A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: pathogenic scores are given by REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas benign predictions come from SIFT, PROVEAN, premPS, ESM1b, Rosetta, Foldetta, 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 further support a benign outcome: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus itself is Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. FoldX alone is Uncertain, but this does not alter the overall consensus. Taken together, the majority of evidence indicates the variant 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 | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -6.928 | Likely Benign | 0.228 | Likely Benign | Likely Benign | -0.50 | Ambiguous | 0.1 | 0.06 | Likely Benign | -0.22 | Likely Benign | 0.37 | Likely Benign | 0.537 | Likely Pathogenic | -1.46 | Neutral | 0.909 | Possibly Damaging | 0.987 | Probably Damaging | -1.51 | Pathogenic | 0.10 | Tolerated | 0.4245 | 0.3996 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1399G>C | D467H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467H 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 only premPS, whereas the remaining evaluated algorithms uniformly predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta yield uncertain results and are treated as unavailable. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of 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 | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -13.348 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.05 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.82 | Ambiguous | 0.32 | Likely Benign | 0.851 | Likely Pathogenic | -6.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.31 | Pathogenic | 0.02 | Affected | 0.1074 | 0.5564 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1400A>G | D467G 2D AISynGAP1 missense variant D467G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—including SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label 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) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive. Consequently, 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 | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.973 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.8 | 2.55 | Destabilizing | 2.21 | Destabilizing | 0.23 | Likely Benign | 0.910 | Likely Pathogenic | -6.81 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0.3455 | 0.4908 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1402A>G | M468V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools, premPS and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Overall, the preponderance of evidence points to a pathogenic 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. | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 1 | -9.461 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 2.69 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.45 | Destabilizing | 0.89 | Ambiguous | 0.570 | Likely Pathogenic | -1.66 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.21 | Pathogenic | 0.08 | Tolerated | 3.37 | 31 | 0.3309 | 0.3845 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||
| c.1404G>A | M468I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M468I is listed in ClinVar with an uncertain significance (ClinVar ID 3657719.0) and is present in gnomAD (6‑33438436‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and Rosetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates a pathogenic impact for M468I, which does not contradict the ClinVar uncertain status but suggests a likely pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 1 | 6-33438436-G-A | 1 | 6.20e-7 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | 0.508 | Likely Pathogenic | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 0.1369 | 0.3354 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||
| c.1404G>C | M468I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. Two methods report uncertainty: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates a pathogenic effect. AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for M468I, 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 | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | 0.508 | Likely Pathogenic | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 0.1369 | 0.3354 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1404G>T | M468I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. Two methods report uncertainty: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates a pathogenic effect; AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for M468I, 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 | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | 0.510 | Likely Pathogenic | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 0.1369 | 0.3354 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1405G>A | A469T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A469T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). The high‑accuracy subset shows AlphaMissense‑Optimized as benign, whereas SGM Consensus and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic effect, 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. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | Uncertain | 1 | -9.540 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 2.26 | Destabilizing | 0.1 | 1.90 | Ambiguous | 2.08 | Destabilizing | 0.34 | Likely Benign | 0.527 | Likely Pathogenic | -1.46 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.21 | Pathogenic | 0.42 | Tolerated | 0.1005 | 0.5884 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.1405G>C | A469P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469P 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 SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the overwhelming consensus of these predictions, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -16.072 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.06 | Destabilizing | 0.3 | 8.83 | Destabilizing | 6.95 | Destabilizing | 1.02 | Destabilizing | 0.774 | Likely Pathogenic | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.33 | Pathogenic | 0.21 | Tolerated | 0.1606 | 0.4092 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1405G>T | A469S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Foldetta, and premPS give uncertain or inconclusive results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts a benign change; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of 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 | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -9.051 | Likely Pathogenic | 0.627 | Likely Pathogenic | Likely Benign | 0.86 | Ambiguous | 0.0 | 2.10 | Destabilizing | 1.48 | Ambiguous | 0.81 | Ambiguous | 0.558 | Likely Pathogenic | -1.53 | Neutral | 0.953 | Possibly Damaging | 0.985 | Probably Damaging | -1.30 | Pathogenic | 0.41 | Tolerated | 0.2113 | 0.4505 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1406C>G | A469G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy methods give mixed results: AlphaMissense‑Optimized indicates benign, Foldetta indicates pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools (12 vs. 4) predict pathogenicity, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -4.438 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 1.99 | Ambiguous | 0.1 | 2.22 | Destabilizing | 2.11 | Destabilizing | 1.01 | Destabilizing | 0.569 | Likely Pathogenic | -2.42 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.32 | Pathogenic | 0.37 | Tolerated | 0.1797 | 0.3078 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1408A>G | M470V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from most in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all score it as deleterious. Only two tools—SIFT and AlphaMissense‑Optimized—classify it as benign, while Rosetta and AlphaMissense‑Default remain inconclusive. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports a benign outcome, but the SGM‑Consensus (derived from a majority of pathogenic calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining pathogenic FoldX with uncertain Rosetta) both predict pathogenicity. Overall, the preponderance of evidence supports a likely pathogenic classification, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Uncertain | 1 | -8.856 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 2.73 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.31 | Destabilizing | 1.31 | Destabilizing | 0.770 | Likely Pathogenic | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.20 | Pathogenic | 0.15 | Tolerated | 3.37 | 34 | 0.2710 | 0.3256 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||
| c.140G>A | R47Q 2D AIThe SynGAP1 missense variant R47Q is listed in ClinVar (ID 436920.0) as Benign and is present in gnomAD (6‑33423549‑G‑A). 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 is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Benign, and no Foldetta data to influence the conclusion. Overall, the majority of evidence points to a benign impact, consistent with the ClinVar classification; there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | Likely Benign | 1 | 6-33423549-G-A | 4 | 2.48e-6 | -4.989 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.57 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3326 | 0.2591 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.1411T>A | S471T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, 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 | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.780 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.59 | Ambiguous | 0.2 | -0.47 | Likely Benign | 0.06 | Likely Benign | 0.20 | Likely Benign | 0.257 | Likely Benign | -1.96 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.18 | Pathogenic | 0.09 | Tolerated | 0.1307 | 0.5046 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1411T>C | S471P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only polyPhen‑2 HumVar, whereas the remaining evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -12.379 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.2 | 9.24 | Destabilizing | 6.45 | Destabilizing | 0.84 | Ambiguous | 0.530 | Likely Pathogenic | -4.03 | Deleterious | 0.552 | Possibly Damaging | 0.141 | Benign | -1.31 | Pathogenic | 0.05 | Affected | 0.2007 | 0.4769 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1411T>G | S471A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471A is not reported in ClinVar and is absent from gnomAD. Across the spectrum of in‑silico predictors, the majority (REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) classify the change as benign, whereas only FATHMM predicts it as pathogenic; Rosetta is inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests pathogenicity, and the predictions do not contradict the absence of ClinVar annotation. Therefore, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.516 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.11 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.25 | Likely Benign | 0.23 | Likely Benign | 0.252 | Likely Benign | -1.93 | Neutral | 0.010 | Benign | 0.037 | Benign | -1.22 | Pathogenic | 0.29 | Tolerated | 0.4439 | 0.3691 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1420G>C | D474H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Pathogenic. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for D474H, 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 | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -13.610 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.0 | 0.00 | Likely Benign | 0.33 | Likely Benign | 0.27 | Likely Benign | 0.739 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.02 | Affected | 0.1398 | 0.4619 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. 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 toward 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 | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | 0.632 | Likely Pathogenic | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 0.2190 | 0.1926 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1426T>A | F476I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F476I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and FATHMM; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive and is treated as unavailable. With seven tools indicating pathogenicity versus five indicating benign, and two high‑accuracy tools supporting pathogenicity, the evidence points to a likely pathogenic effect. 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. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.617 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.90 | Destabilizing | 0.1 | 3.09 | Destabilizing | 3.50 | Destabilizing | 0.39 | Likely Benign | 0.239 | Likely Benign | -1.23 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.50 | Benign | 0.37 | Tolerated | 0.1383 | 0.2202 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||
| c.1429A>G | M477V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477V is listed in ClinVar with no submitted interpretation and is present in the gnomAD database (variant ID 6‑33438461‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only two tools predict a pathogenic outcome: polyPhen2_HumDiv and FATHMM. Predictions from FoldX and Foldetta are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains inconclusive. Taken together, the majority of evidence supports a benign classification for M477V, and this assessment does not contradict the ClinVar status, which currently has no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438461-A-G | 1 | 6.20e-7 | -3.995 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 1.64 | Ambiguous | 0.3 | 0.42 | Likely Benign | 1.03 | Ambiguous | 0.24 | Likely Benign | 0.209 | Likely Benign | -1.04 | Neutral | 0.716 | Possibly Damaging | 0.204 | Benign | -1.19 | Pathogenic | 0.22 | Tolerated | 3.37 | 34 | 0.3093 | 0.3445 | 1 | 2 | 2.3 | -32.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||
| c.142T>A | F48I 2D AIThe SynGAP1 missense variant F48I 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, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while SIFT and AlphaMissense‑Default predict a pathogenic impact. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further clarify the variant’s likely benign nature: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors benign; AlphaMissense‑Optimized remains uncertain, and Foldetta (which would evaluate protein‑folding stability) is unavailable. Overall, the balance of evidence points to a benign classification, 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. | 0.298791 | Structured | 0.440452 | Uncertain | 0.558 | 0.707 | 0.125 | -7.994 | In-Between | 0.808 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.67 | Neutral | 0.092 | Benign | 0.050 | Benign | 3.99 | Benign | 0.00 | Affected | 0.2561 | 0.2301 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (variant ID 6‑33438468‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic impact. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and ESM1b. 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 effect, and this consensus does not contradict the ClinVar “Uncertain” status; 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 | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | 0.191 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 0.2448 | 0.1812 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1438G>A | E480K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480K is catalogued in gnomAD (ID 6‑33438470‑G‑A) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from FoldX and SIFT, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E480K 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 | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-A | 1 | 6.20e-7 | -14.059 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.08 | Ambiguous | 0.74 | Ambiguous | 0.83 | Ambiguous | 0.768 | Likely Pathogenic | -3.45 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.1828 | 0.6813 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1441C>G | H481D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic signal: the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Uncertain results from AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect for H481D, 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 | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.822 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | -0.09 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.23 | Likely Benign | 0.70 | Ambiguous | 0.273 | Likely Benign | -5.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.50 | Tolerated | 0.2109 | 0.1058 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1449A>G | I483M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I483M missense variant is not reported in ClinVar (ClinVar status: not present) but is catalogued in gnomAD (gnomAD ID: 6‑33438481‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are premPS, 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, classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as benign. No conclusive folding‑stability result is available from Rosetta. Overall, the majority of high‑accuracy tools (two benign, one pathogenic) lean toward a benign interpretation, and this assessment is not contradicted by any ClinVar annotation. 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 Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | 6-33438481-A-G | 1 | 6.20e-7 | -8.839 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 0.02 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.38 | Likely Benign | 1.06 | Destabilizing | 0.261 | Likely Benign | -2.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 3.37 | 32 | 0.0607 | 0.1959 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||
| c.1450T>A | F484I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the preponderance of evidence, 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 | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -16.197 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.62 | Destabilizing | 0.2 | 5.62 | Destabilizing | 5.62 | Destabilizing | 1.33 | Destabilizing | 0.399 | Likely Benign | -5.70 | Deleterious | 0.894 | Possibly Damaging | 0.332 | Benign | 2.74 | Benign | 0.00 | Affected | 0.1516 | 0.1885 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1460A>G | N487S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is also inconclusive. Overall, the preponderance of evidence from multiple in silico predictors and the SGM Consensus indicates that the variant is most likely pathogenic. 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 | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -10.297 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 1.42 | Ambiguous | 0.0 | 1.49 | Ambiguous | 1.46 | Ambiguous | 0.65 | Ambiguous | 0.459 | Likely Benign | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.74 | Benign | 0.01 | Affected | 0.3065 | 0.3656 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1461C>A | N487K 2D AIThe SynGAP1 missense variant N487K 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 REVEL and FATHMM. The remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability predictions are available. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.489 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1461C>G | N487K 2D AIThe SynGAP1 missense variant N487K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑related methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.488 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1462A>G | T488A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the majority of tools (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity; Rosetta and premPS are uncertain. High‑accuracy assessments further support a deleterious effect: 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. Taken together, the preponderance of evidence indicates that T488A 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 | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -11.341 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.06 | Destabilizing | 0.57 | Ambiguous | 0.497 | Likely Benign | -4.64 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.24 | Benign | 0.01 | Affected | 0.2871 | 0.2872 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1462A>T | T488S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T488S 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, and Rosetta) 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 majority of standard tools lean toward a benign interpretation, but the high‑accuracy consensus is split, leaving the variant’s impact ambiguous. No ClinVar annotation contradicts these predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -7.662 | In-Between | 0.745 | Likely Pathogenic | Likely Benign | 0.35 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.63 | Ambiguous | 0.77 | Ambiguous | 0.257 | Likely Benign | -3.51 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.73 | Benign | 0.31 | Tolerated | 0.2256 | 0.2813 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||
| c.1468G>T | A490S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A490S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) indicate a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts it to be likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. No other tools provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests that A490S 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. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -8.307 | Likely Pathogenic | 0.426 | Ambiguous | Likely Benign | 0.76 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.16 | Ambiguous | 0.89 | Ambiguous | 0.766 | Likely Pathogenic | -2.82 | Deleterious | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.41 | Pathogenic | 0.02 | Affected | 0.2338 | 0.3116 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1469C>G | A490G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Pathogenic). Predictions that are uncertain or inconclusive are FoldX, Foldetta, 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 uncertain. Overall, the majority of evidence points to a pathogenic impact for A490G. 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 Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -9.767 | Likely Pathogenic | 0.384 | Ambiguous | Likely Benign | 1.24 | Ambiguous | 0.0 | 2.00 | Destabilizing | 1.62 | Ambiguous | 1.13 | Destabilizing | 0.744 | Likely Pathogenic | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.46 | Pathogenic | 0.01 | Affected | 0.2051 | 0.2228 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1471A>T | T491S 2D AIThe SynGAP1 missense variant T491S 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 only SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX or Rosetta is available to support a stability change. Overall, the preponderance of evidence points to a pathogenic effect for T491S, 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 | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -7.273 | In-Between | 0.924 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.7 | 1.27 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.704 | Likely Pathogenic | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.19 | Tolerated | 0.3119 | 0.2815 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1472C>G | T491S 2D AIThe SynGAP1 missense variant T491S 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 only SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX or Rosetta is available to support a stability change. Overall, the preponderance of evidence points to a pathogenic effect for T491S, 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 | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -7.273 | In-Between | 0.924 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.7 | 1.27 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.666 | Likely Pathogenic | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.19 | Tolerated | 0.3119 | 0.2815 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1474A>C | K492Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions are made by premPS, 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 pathogenicity, SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.685 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.64 | Ambiguous | 1.13 | Destabilizing | 0.463 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.02 | Affected | 0.3534 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1474A>G | K492E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492E 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. The remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which contradicts its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | Conflicting | 2 | -16.175 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.72 | Ambiguous | 1.42 | Destabilizing | 0.510 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2968 | 0.0650 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1476A>C | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly 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 pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, 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 | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1476A>T | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly 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 pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, 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 | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1477G>A | A493T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A493T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a deleterious effect: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, premPS, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as pathogenic or likely pathogenic. Only Rosetta predicts a benign outcome; FoldX, Foldetta, and AlphaMissense‑Optimized are uncertain or unavailable. High‑accuracy tools give the following: AlphaMissense‑Optimized – uncertain; SGM Consensus – likely pathogenic; Foldetta – uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for A493T. 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 | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -10.366 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.82 | Ambiguous | 0.0 | 0.39 | Likely Benign | 0.61 | Ambiguous | 1.10 | Destabilizing | 0.727 | Likely Pathogenic | -3.41 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.04 | Affected | 0.0964 | 0.3972 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1477G>C | A493P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious effects. No tool in the dataset indicates a benign outcome. High‑accuracy methods reinforce this consensus: 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. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -15.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.96 | Destabilizing | 0.1 | 10.79 | Destabilizing | 7.88 | Destabilizing | 1.32 | Destabilizing | 0.883 | Likely Pathogenic | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.02 | Affected | 0.1490 | 0.2907 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1477G>T | A493S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493S 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 PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as unavailable. Based on the consensus of the available predictions, 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 | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -6.271 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.10 | Ambiguous | 0.88 | Ambiguous | 0.53 | Ambiguous | 0.507 | Likely Pathogenic | -2.12 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 0.1821 | 0.2763 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1478C>G | A493G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all predict pathogenicity, while only AlphaMissense‑Optimized predicts a benign outcome. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains pathogenic; Foldetta likewise yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for A493G, 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 | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -11.379 | Likely Pathogenic | 0.571 | Likely Pathogenic | Likely Benign | 1.85 | Ambiguous | 0.0 | 1.63 | Ambiguous | 1.74 | Ambiguous | 1.40 | Destabilizing | 0.764 | Likely Pathogenic | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.40 | Pathogenic | 0.02 | Affected | 0.1673 | 0.2228 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1483G>A | E495K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | 0.869 | Likely Pathogenic | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1974 | 0.5039 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.148A>T | I50F 2D AIThe SynGAP1 missense variant I50F 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 not available. Overall, the majority of evidence points to a benign impact for I50F, 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 | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.631 | Likely Benign | 0.681 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -1.27 | Neutral | 0.334 | Benign | 0.074 | Benign | 3.75 | Benign | 0.00 | Affected | 0.0483 | 0.2560 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.14G>A | R5Q 2D AIThe SynGAP1 missense variant R5Q is reported in gnomAD (variant ID 6‑33420278‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. This prediction 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 | 0.595080 | Disordered | 0.547847 | Binding | 0.363 | 0.920 | 0.750 | 6-33420278-G-A | 2 | 1.30e-6 | -4.261 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.06 | Neutral | 0.403 | Benign | 0.007 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3740 | 0.3122 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||||
| c.1501A>T | I501F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I501F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain (a stability method that integrates FoldX‑MD and Rosetta outputs). No predictions are missing or inconclusive. Overall, the majority of evidence points toward a pathogenic impact, 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 | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -12.113 | Likely Pathogenic | 0.664 | Likely Pathogenic | Likely Benign | 3.06 | Destabilizing | 0.1 | 0.26 | Likely Benign | 1.66 | Ambiguous | 0.71 | Ambiguous | 0.385 | Likely Benign | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.0574 | 0.1594 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| 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.1505G>A | G502D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. 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 | Uncertain | 1 | -14.796 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.9 | 5.69 | Destabilizing | 4.74 | Destabilizing | 1.38 | Destabilizing | 0.915 | Likely Pathogenic | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | -1.66 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1715 | 0.1172 | 1 | -1 | -3.1 | 58.04 | 224.2 | -80.0 | -0.8 | 0.7 | 0.6 | 0.3 | X | X | X | Potentially Pathogenic | Gly502 is located in a hinge in the middle of an α-helix (res. Leu489-Glu519). In the WT, Gly502 acts as an α-helix breaker due to its lack of a side chain, facilitating a bend in the middle of the α-helix. In the variant simulations, the carboxylate group of Asp502 forms hydrogen bonds with neighboring residues (e.g., Ser677, Lys504), disrupting the hinge. Additionally, Asp502 struggles to fit into the α-helix hinge and cannot generate a similar bend as Gly502, which would drastically affect the secondary structure during folding. Thus, the deleterious effect seen in the simulations is likely an underestimate of the impact of the residue swap on the protein structure during protein folding. | ||||||||||||||
| c.1505G>C | G502A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G502A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Foldetta, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—concludes pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for G502A, and this assessment does not conflict with the absence of ClinVar annotation. 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 | -10.191 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.4 | -0.53 | Ambiguous | 0.15 | Likely Benign | 0.54 | Ambiguous | 0.725 | Likely Pathogenic | -5.64 | Deleterious | 0.512 | Possibly Damaging | 0.157 | Benign | -1.59 | Pathogenic | 0.17 | Tolerated | 0.3548 | 0.3393 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1507C>A | Q503K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503K is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 tools lean toward a benign effect, and this conclusion is not contradicted by ClinVar data, which contains no entry for this variant. Thus, the variant is most likely benign, with no ClinVar evidence contradicting this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -12.276 | Likely Pathogenic | 0.217 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.1 | -0.26 | Likely Benign | -0.14 | Likely Benign | 0.70 | Ambiguous | 0.603 | Likely Pathogenic | -3.37 | Deleterious | 0.676 | Possibly Damaging | 0.297 | Benign | -1.42 | Pathogenic | 0.12 | Tolerated | 0.1601 | 0.2419 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1508A>G | Q503R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. The high‑accuracy methods give a benign result for AlphaMissense‑Optimized, a pathogenic result for the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign result for Foldetta (combining FoldX‑MD and Rosetta). Overall, the majority of tools and the high‑accuracy methods lean toward a benign effect. Thus, the variant is most likely benign, 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 | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -11.396 | Likely Pathogenic | 0.232 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.3 | 0.60 | Ambiguous | 0.10 | Likely Benign | 0.50 | Likely Benign | 0.640 | Likely Pathogenic | -3.34 | Deleterious | 0.577 | Possibly Damaging | 0.395 | Benign | -1.42 | Pathogenic | 0.06 | Tolerated | 0.1426 | 0.0963 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1510A>C | K504Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K504Q 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, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign stability change. Overall, seven tools support a benign outcome while four support pathogenicity, with no ClinVar evidence to contradict this assessment. 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. | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -6.685 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.2 | -0.01 | Likely Benign | 0.06 | Likely Benign | 0.91 | Ambiguous | 0.269 | Likely Benign | -3.07 | Deleterious | 0.945 | Possibly Damaging | 0.918 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0.3104 | 0.0780 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.1512A>C | K504N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504N is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 tools (8/13) predict pathogenicity, while 4 predict benign and one is uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -8.908 | Likely Pathogenic | 0.720 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | 0.430 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 0.2470 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1512A>T | K504N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K504N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, AlphaMissense‑Optimized, and the folding‑stability method Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, 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 indicating a benign folding‑stability outcome. Overall, the majority of predictions (8 out of 13) support a pathogenic interpretation. Thus, 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 | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -8.908 | Likely Pathogenic | 0.720 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | 0.430 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 0.2470 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1519A>C | K507Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507Q 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, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta, premPS, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Taken together, the preponderance of evidence indicates that the variant 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. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -7.698 | In-Between | 0.180 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.21 | Likely Benign | -0.52 | Ambiguous | 0.443 | Likely Benign | 0.22 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.86 | Tolerated | 0.2952 | 0.0713 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.151A>T | I51F 2D AIThe SynGAP1 missense variant I51F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while 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 results are unavailable. Overall, the preponderance of evidence points to a benign effect for I51F, 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 | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -5.687 | Likely Benign | 0.526 | Ambiguous | Likely Benign | 0.114 | Likely Benign | -0.87 | Neutral | 0.099 | Benign | 0.039 | Benign | 4.13 | Benign | 0.00 | Affected | 0.0565 | 0.3070 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.1521G>C | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas a pathogenic signal is reported by REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta’s stability prediction is unavailable. Overall, the majority of tools (10 out of 14 with definitive calls) predict a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1521G>T | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic effect comprise REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta are uncertain. 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 majority of tools (10 pathogenic vs. 4 benign) predict a deleterious impact. Thus, 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 | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1522G>C | D508H 2D AISynGAP1 D508H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show an even split: benign calls come from REVEL, FoldX, premPS, SIFT, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain outcome from AlphaMissense‑Optimized, and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). Overall, the balance of evidence leans toward pathogenicity, 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 Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.074 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.336 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 0.1804 | 0.5096 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1523A>G | D508G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive and is treated as unavailable. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus, and a pathogenic prediction from Foldetta. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect. This conclusion does not contradict ClinVar, as no ClinVar entry exists for this variant. 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 | -8.478 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.2 | 3.20 | Destabilizing | 2.04 | Destabilizing | 0.13 | Likely Benign | 0.368 | Likely Benign | -6.61 | Deleterious | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 3.30 | Benign | 0.07 | Tolerated | 0.3821 | 0.4528 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1525G>A | A509T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509T 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, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore unavailable for interpretation. Overall, the majority of evidence points to a benign impact, and this conclusion 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. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -8.961 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.95 | Ambiguous | 0.4 | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.04 | Likely Benign | 0.360 | Likely Benign | -2.15 | Neutral | 0.031 | Benign | 0.058 | Benign | -1.25 | Pathogenic | 0.32 | Tolerated | 0.1344 | 0.5593 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| 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.1525G>T | A509S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509S 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 PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Four tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS). High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta is also inconclusive. Overall, the majority of standard predictors lean toward pathogenicity, while the most reliable single‑tool prediction (AlphaMissense‑Optimized) suggests benign. Given the balance of 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. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -9.997 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.23 | Ambiguous | 0.59 | Ambiguous | 0.621 | Likely Pathogenic | -2.18 | Neutral | 0.119 | Benign | 0.468 | Possibly Damaging | -1.35 | Pathogenic | 0.01 | Affected | 0.2410 | 0.4384 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| 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.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.1532G>C | G511A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. 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 remains uncertain. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that 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 | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -9.621 | Likely Pathogenic | 0.844 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 0.3793 | 0.2778 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1537T>A | F513I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513I is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely converge on a deleterious effect: SIFT is the sole benign caller, whereas REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. Grouping by consensus, the single benign prediction (SIFT) is outweighed by the 13 pathogenic calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; 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 a pathogenic outcome. Consequently, 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 | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -12.003 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.4 | 2.18 | Destabilizing | 2.80 | Destabilizing | 1.12 | Destabilizing | 0.766 | Likely Pathogenic | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.24 | Pathogenic | 0.22 | Tolerated | 0.1473 | 0.1766 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1546G>A | A516T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include SIFT, Rosetta, and Foldetta, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as benign. With the pathogenic predictions outweighing the benign ones, the variant is most likely pathogenic. This conclusion does not contradict 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 | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -9.716 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.2 | -0.14 | Likely Benign | 0.22 | Likely Benign | 0.63 | Ambiguous | 0.520 | Likely Pathogenic | -3.21 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.17 | Tolerated | 0.1586 | 0.5739 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1546G>C | A516P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies it as pathogenic. Based on the consensus of these predictions, 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 | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -15.348 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.3 | 10.96 | Destabilizing | 6.82 | Destabilizing | 0.83 | Ambiguous | 0.750 | Likely Pathogenic | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.06 | Tolerated | 0.2214 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1546G>T | A516S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A516S 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, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools remain uncertain: premPS and AlphaMissense‑Default. 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. Overall, the majority of evidence points to a benign effect, 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. | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -9.639 | Likely Pathogenic | 0.562 | Ambiguous | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.24 | Likely Benign | 0.23 | Likely Benign | 0.52 | Ambiguous | 0.448 | Likely Benign | -2.45 | Neutral | 0.973 | Probably Damaging | 0.993 | Probably Damaging | -1.24 | Pathogenic | 0.17 | Tolerated | 0.2730 | 0.4730 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1547C>G | A516G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A516G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are limited to SIFT, whereas the remaining seven tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No stability‑change predictions are definitive. Overall, the majority of evidence points to a pathogenic impact for A516G. 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 | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -10.673 | Likely Pathogenic | 0.864 | Likely Pathogenic | Ambiguous | 0.86 | Ambiguous | 0.2 | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.88 | Ambiguous | 0.557 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 0.2379 | 0.4370 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.154T>A | S52T 2D AIThe SynGAP1 missense variant S52T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and SIFT. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, 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 | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.731 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.06 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 0.1505 | 0.6751 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.154T>G | S52A 2D AIThe SynGAP1 missense variant S52A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool predicting a pathogenic outcome is SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly supports 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 | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.326 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.69 | Neutral | 0.140 | Benign | 0.355 | Benign | 4.17 | Benign | 0.00 | Affected | 0.5389 | 0.5073 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.1555G>A | E519K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519K missense variant is listed in gnomAD (ID 6‑33438798‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by FoldX, 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 E519K, 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 | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | 6-33438798-G-A | 1 | 6.20e-7 | -13.532 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | -0.55 | Ambiguous | 0.0 | -0.60 | Ambiguous | -0.58 | Ambiguous | 0.06 | Likely Benign | 0.328 | Likely Benign | -3.48 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 3.28 | Benign | 0.03 | Affected | 3.37 | 35 | 0.2545 | 0.3379 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1558T>A | S520T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520T is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS and PROVEAN, while pathogenic predictions are made by SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four high‑accuracy methods were examined: AlphaMissense‑Optimized returned an uncertain result; 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, was also uncertain. With three of the four high‑accuracy tools indicating pathogenicity and only two tools suggesting benign, the overall evidence points to 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 | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.432 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.52 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.565 | Likely Pathogenic | -2.41 | Neutral | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.28 | Pathogenic | 0.02 | Affected | 0.1296 | 0.5199 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, 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 Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | 0.855 | Likely Pathogenic | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.2154 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1558T>G | S520A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S520A 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 FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized, whereas a larger group—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus is split, but the pathogenic predictions dominate. Thus, 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 | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.417 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.03 | Likely Benign | 0.2 | 0.19 | Likely Benign | 0.11 | Likely Benign | 0.56 | Ambiguous | 0.523 | Likely Pathogenic | -2.55 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.4887 | 0.3636 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1568A>G | N523S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523S 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) returned uncertain or inconclusive results. For high‑accuracy assessment, AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain folding‑stability change. Taken together, the majority of evidence (five benign versus three pathogenic predictions) points to a benign effect, 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. | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -6.188 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.2 | 0.66 | Ambiguous | 0.65 | Ambiguous | 0.17 | Likely Benign | 0.492 | Likely Benign | -4.31 | Deleterious | 0.976 | Probably Damaging | 0.410 | Benign | -1.27 | Pathogenic | 0.27 | Tolerated | 0.2213 | 0.4178 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| 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.1573G>A | E525K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E525K is reported in gnomAD (ID 6‑33438816‑G‑A) but has no ClinVar entry. Functional prediction tools show a split assessment: benign predictions come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while the Foldetta stability analysis predicts a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion 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 | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | 6-33438816-G-A | 1 | 6.20e-7 | -15.628 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.13 | Likely Benign | 0.5 | 0.34 | Likely Benign | 0.11 | Likely Benign | 0.96 | Ambiguous | 0.629 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.71 | Benign | 0.00 | Affected | 3.37 | 35 | 0.2349 | 0.4293 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1579G>C | D527H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and premPS, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Uncertain results come from Rosetta and Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as pathogenic, and Foldetta as inconclusive. Based on the preponderance of pathogenic predictions and the lack of benign 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 | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -13.334 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 1.2 | 1.26 | Ambiguous | 0.83 | Ambiguous | 0.49 | Likely Benign | 0.901 | Likely Pathogenic | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -2.39 | Pathogenic | 0.00 | Affected | 0.1092 | 0.4346 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1580A>G | D527G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate pathogenicity. FoldX is uncertain and therefore not counted as evidence for either side. High‑accuracy methods reinforce the pathogenic assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No contradictory evidence exists in ClinVar. **Thus, the variant is most likely pathogenic based on the collective predictions, with no ClinVar status to contradict this assessment.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -15.177 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 1.0 | 4.22 | Destabilizing | 2.97 | Destabilizing | 0.33 | Likely Benign | 0.933 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.39 | Pathogenic | 0.01 | Affected | 0.2847 | 0.4366 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1582C>G | P528A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, while the remaining pathogenic‑predicting tools are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy methods give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by 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 | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.562 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 1.57 | Ambiguous | 0.1 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.69 | Ambiguous | 0.548 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3146 | 0.3914 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1582C>T | P528S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No folding‑stability metrics (FoldX, Rosetta, premPS) provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests 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 | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.729 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.58 | Ambiguous | 0.80 | Ambiguous | 0.617 | Likely Pathogenic | -7.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3115 | 0.3982 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| 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.158G>C | G53A 2D AIThe SynGAP1 missense variant G53A 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, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) also as 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 | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -6.329 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -1.00 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | 0.4093 | 0.5550 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.1594A>G | T532A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts 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 (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -2.907 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.0 | 0.13 | Likely Benign | 0.15 | Likely Benign | 0.11 | Likely Benign | 0.165 | Likely Benign | -0.80 | Neutral | 0.032 | Benign | 0.023 | Benign | -1.15 | Pathogenic | 0.14 | Tolerated | 0.3573 | 0.3114 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1594A>T | T532S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532S 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, 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 Benign | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | 0.616 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.1 | -0.23 | Likely Benign | -0.04 | Likely Benign | -0.10 | Likely Benign | 0.160 | Likely Benign | 0.53 | Neutral | 0.005 | Benign | 0.013 | Benign | -1.22 | Pathogenic | 1.00 | Tolerated | 0.2988 | 0.2866 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1597G>C | A533P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, 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 benign. Only FATHMM predicts pathogenic. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as unavailable. Overall, the consensus of the majority of tools indicates a benign impact. This prediction 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 Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.951 | Likely Benign | 0.081 | Likely Benign | Likely Benign | -0.93 | Ambiguous | 0.3 | -0.92 | Ambiguous | -0.93 | Ambiguous | -0.18 | Likely Benign | 0.187 | Likely Benign | -0.48 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.26 | Pathogenic | 0.09 | Tolerated | 0.1925 | 0.5299 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1597G>T | A533S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533S 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains all tools except FATHMM, which stands alone in the pathogenic group. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign effect. Based on the preponderance of 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 | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.740 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.10 | Likely Benign | -0.14 | Likely Benign | 0.193 | Likely Benign | 0.33 | Neutral | 0.009 | Benign | 0.039 | Benign | -1.14 | Pathogenic | 0.45 | Tolerated | 0.2612 | 0.5334 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1598C>G | A533G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533G resides 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 include SGM‑Consensus (Likely Benign), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; Rosetta is uncertain and therefore not counted as evidence. High‑accuracy assessments—all of which are available—show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Benign, reinforcing the benign consensus. Based on the collective predictions, 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 | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.412 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.64 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | 0.185 | Likely Benign | -1.94 | Neutral | 0.258 | Benign | 0.099 | Benign | -1.23 | Pathogenic | 0.23 | Tolerated | 0.2348 | 0.4737 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1600T>A | S534T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534T 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 benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. 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. Thus, the overall evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.925 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.28 | Likely Benign | 0.19 | Likely Benign | 0.200 | Likely Benign | -2.42 | Neutral | 0.676 | Possibly Damaging | 0.933 | Probably Damaging | 3.32 | Benign | 0.07 | Tolerated | 0.1238 | 0.5064 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1600T>G | S534A 2D 3DClick to see structure in 3D Viewer AISynGAP1 S534A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests a deleterious effect. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.691 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.01 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.00 | Likely Benign | 0.11 | Likely Benign | 0.163 | Likely Benign | -1.70 | Neutral | 0.880 | Possibly Damaging | 0.994 | Probably Damaging | 3.36 | Benign | 0.42 | Tolerated | 0.5042 | 0.3131 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.1603A>G | S535G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S535G, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.619 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.19 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.56 | Ambiguous | 0.64 | Ambiguous | 0.247 | Likely Benign | -1.75 | Neutral | 0.606 | Possibly Damaging | 0.114 | Benign | -1.30 | Pathogenic | 0.19 | Tolerated | 0.2858 | 0.4644 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1604G>A | S535N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) uniformly predict a benign effect, whereas only FATHMM assigns a pathogenic label. High‑accuracy assessments corroborate the benign consensus: 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 outputs) predicts benign stability. Thus, the variant is most likely benign based on the available predictions, 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 | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -4.957 | Likely Benign | 0.196 | Likely Benign | Likely Benign | -0.46 | Likely Benign | 0.2 | -0.26 | Likely Benign | -0.36 | Likely Benign | 0.18 | Likely Benign | 0.176 | Likely Benign | -0.05 | Neutral | 0.070 | Benign | 0.032 | Benign | -1.25 | Pathogenic | 0.29 | Tolerated | 0.1390 | 0.4784 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1604G>C | S535T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535T is catalogued in ClinVar as benign (ClinVar ID 537005.0) and is observed in gnomAD (variant ID 6‑33438847‑G‑C). In silico prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. Only FATHMM predicts 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 confirm this: AlphaMissense‑Optimized is benign; the SGM Consensus is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the consensus of predictive tools and high‑accuracy methods indicates that the variant is most likely benign, consistent with its ClinVar classification and presence in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | Benign | 1 | 6-33438847-G-C | 14 | 8.67e-6 | -3.886 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.09 | Likely Benign | 0.17 | Likely Benign | 0.177 | Likely Benign | -0.81 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.25 | Pathogenic | 0.25 | Tolerated | 3.37 | 35 | 0.1456 | 0.6291 | 1 | 1 | 0.1 | 14.03 | 201.3 | -17.3 | -0.1 | 0.7 | -0.2 | 0.1 | X | Potentially Benign | Ser535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. 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. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.1609G>C | A537P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and Rosetta; FoldX and Foldetta are inconclusive. The high‑accuracy consensus (SGM‑Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN indicates a likely benign outcome, while AlphaMissense‑Optimized also predicts benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A537P, 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 Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 0.404 | Likely Benign | 0.102 | Likely Benign | Likely Benign | -0.61 | Ambiguous | 0.6 | 2.43 | Destabilizing | 0.91 | Ambiguous | -0.18 | Likely Benign | 0.218 | Likely Benign | 0.67 | Neutral | 0.020 | Benign | 0.022 | Benign | -1.29 | Pathogenic | 0.35 | Tolerated | 0.2152 | 0.3807 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1609G>T | A537S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537S is reported in gnomAD (6-33438852-G-T) and has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. When predictions are grouped, the majority of tools (ten) support benign, whereas three tools support pathogenic. High‑accuracy assessments further reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Consequently, 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 | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 6-33438852-G-T | 1 | 6.20e-7 | -3.602 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | 0.46 | Likely Benign | 0.37 | Likely Benign | 0.28 | Likely Benign | 0.206 | Likely Benign | -0.66 | Neutral | 0.528 | Possibly Damaging | 0.592 | Possibly Damaging | -1.25 | Pathogenic | 0.60 | Tolerated | 3.37 | 35 | 0.2729 | 0.4431 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||
| c.1610C>G | A537G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. Uncertain results come from Rosetta, Foldetta, and premPS. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence supports a benign impact for A537G, 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 | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | -4.302 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.64 | Ambiguous | 0.68 | Ambiguous | 0.290 | Likely Benign | -1.85 | Neutral | 0.977 | Probably Damaging | 0.672 | Possibly Damaging | -1.30 | Pathogenic | 0.36 | Tolerated | 0.2289 | 0.3387 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1615C>G | H539D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the only inconclusive result is FoldX, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -16.450 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | 3.27 | Destabilizing | 2.25 | Destabilizing | 1.08 | Destabilizing | 0.889 | Likely Pathogenic | -8.05 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.02 | Affected | 0.2008 | 0.0708 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1618C>A | Q540K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540K 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 FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 (10 pathogenic vs. 5 benign) indicate a likely pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -11.418 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | -0.37 | Likely Benign | 0.0 | -0.03 | Likely Benign | -0.20 | Likely Benign | 0.76 | Ambiguous | 0.808 | Likely Pathogenic | -3.98 | Deleterious | 0.985 | Probably Damaging | 0.965 | Probably Damaging | -1.31 | Pathogenic | 0.06 | Tolerated | 0.1508 | 0.2472 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1619A>G | Q540R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540R has no ClinVar entry and is present in gnomAD (ID 6‑33438862‑A‑G). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools report uncertainty: premPS 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) as benign. Overall, the majority of evidence points to a benign impact, with only a minority of tools indicating pathogenicity. This conclusion does not contradict ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | 6-33438862-A-G | 1 | 6.19e-7 | -13.312 | Likely Pathogenic | 0.540 | Ambiguous | Likely Benign | -0.06 | Likely Benign | 0.0 | -0.07 | Likely Benign | -0.07 | Likely Benign | 0.88 | Ambiguous | 0.795 | Likely Pathogenic | -3.98 | Deleterious | 0.991 | Probably Damaging | 0.985 | Probably Damaging | -1.28 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | 0.1328 | 0.1886 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||
| c.161A>G | N54S 2D AIThe SynGAP1 missense variant N54S 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, 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 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 | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -5.358 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -0.17 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 0.3740 | 0.7048 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.1621G>A | A541T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A541T missense variant is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that report a benign effect include Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools (FoldX and AlphaMissense‑Default) returned uncertain results. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic. Overall, the majority of tools (six benign vs. five pathogenic) suggest a benign impact, 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. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -8.555 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.52 | Ambiguous | 0.0 | -0.07 | Likely Benign | 0.23 | Likely Benign | 0.45 | Likely Benign | 0.500 | Likely Pathogenic | -2.02 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.28 | Pathogenic | 0.15 | Tolerated | 0.1088 | 0.4164 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1621G>C | A541P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. 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) predicts pathogenicity. No predictions are inconclusive or missing. Overall, the collective evidence points to a pathogenic effect for A541P, 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. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | -14.733 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.47 | Destabilizing | 0.3 | 7.26 | Destabilizing | 4.87 | Destabilizing | 0.86 | Ambiguous | 0.594 | Likely Pathogenic | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.1706 | 0.2707 | 1 | -1 | -3.4 | 26.04 | 170.4 | -11.2 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Proline lacks a free backbone amide group, and thus, Pro541 is unable to form a hydrogen bond with the carbonyl group of Ala537 in the variant simulations. Consequently, Pro541 disrupts the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. | ||||||||||||||||
| c.1621G>T | A541S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as tolerated. In contrast, only three tools—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: 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 the 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 | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -5.941 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | 0.18 | Likely Benign | 0.17 | Likely Benign | 0.35 | Likely Benign | 0.347 | Likely Benign | -0.45 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 0.2182 | 0.3340 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1622C>G | A541G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward 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. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | 6-33438865-C-G | 2 | 1.24e-6 | -7.233 | In-Between | 0.341 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.81 | Ambiguous | 0.76 | Ambiguous | 0.421 | Likely Benign | -1.48 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.57 | Tolerated | 3.37 | 35 | 0.1787 | 0.2428 | 1 | 0 | -2.2 | -14.03 | 170.1 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted. | ||||||||||||||
| c.1625A>G | N542S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N542S is listed in ClinVar as benign (ClinVar ID 833567.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus predicting likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, which is in conflict with the ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | Likely Benign | 1 | -9.675 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.98 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.99 | Ambiguous | 0.91 | Ambiguous | 0.752 | Likely Pathogenic | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.36 | Pathogenic | 0.13 | Tolerated | 3.37 | 35 | 0.3054 | 0.5719 | 1 | 1 | 2.7 | -27.03 | 212.5 | 32.1 | 0.0 | 0.0 | -0.6 | 0.3 | X | Potentially Pathogenic | Asn542 is located in an α-helix (res. Ala533-Val560) next to an α-α loop between two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxamide group of the Asn542 side chain forms a hydrogen bond with the backbone carbonyl group of Asn523 and packs favourably against Glu522 from the loop. In contrast, in the variant simulations, the hydroxyl group of the Ser542 side chain is unable to maintain either the hydrogen bond with Asn523 or the packing against the Glu522 side chain. Instead, the hydroxyl group of Ser542 occasionally forms a hydrogen bond with the backbone carbonyl group of Glu538.Altogether, the residue swap results in a looser helix-loop association, which is especially evident in the third replica simulation, where Asn523 moves away from its initial placement next to the α-helix. In short, based on the simulations, the residue swap weakens the GAP domain tertiary structure assembly, which in turn could negatively affect protein folding. | ||||||||||||||||
| c.1626C>A | N542K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542K is not reported in ClinVar and has no entries in gnomAD. Prediction tools largely disagree: benign calls come from FoldX, SIFT, and Foldetta; pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (Rosetta and premPS) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, whereas Foldetta predicts benign. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence (nine pathogenic vs three benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -11.967 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.09 | Likely Benign | 0.75 | Ambiguous | 0.610 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.23 | Pathogenic | 0.10 | Tolerated | 0.1870 | 0.4349 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1626C>G | N542K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542K 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 FoldX, SIFT, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (Rosetta and premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also pathogenic, while Foldetta predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence (nine pathogenic vs. three benign) 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 | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -11.967 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.09 | Likely Benign | 0.75 | Ambiguous | 0.610 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.23 | Pathogenic | 0.10 | Tolerated | 0.1870 | 0.4349 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| 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.1631G>A | R544Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R544Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438874‑G‑A). Prediction tools that classify the change as benign include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta 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 remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is not contradictory to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038858 | Structured | 0.016004 | Uncertain | 0.967 | 0.333 | 0.000 | Uncertain | 1 | 6-33438874-G-A | 1 | 6.20e-7 | -10.281 | Likely Pathogenic | 0.596 | Likely Pathogenic | Likely Benign | 0.19 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.53 | Ambiguous | 1.40 | Destabilizing | 0.542 | Likely Pathogenic | -2.41 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 0.2103 | 0.1959 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1635G>A | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions arise from FoldX, Rosetta, and SIFT, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains inconclusive. High‑accuracy methods provide mixed evidence: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also suggests likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of conventional tools and the SGM Consensus lean toward pathogenicity, whereas the Foldetta result is an outlier. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict its ClinVar uncertain status. 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 | Uncertain | 1 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | 0.592 | Likely Pathogenic | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 0.1091 | 0.2114 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1635G>C | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I 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, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus result is a majority vote of four pathogenic predictors (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), confirming its pathogenic label. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; no other high‑accuracy tools are available. Overall, the majority of predictions support a pathogenic effect, with only a minority indicating benign. 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. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | 0.592 | Likely Pathogenic | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 0.1091 | 0.2114 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1635G>T | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that 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 | 0.012875 | Uncertain | 0.955 | 0.311 | 0.000 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | 0.592 | Likely Pathogenic | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 0.1091 | 0.2114 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.163C>A | Q55K 2D AIThe SynGAP1 missense variant Q55K is listed in ClinVar (ID 520688.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33423572‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 is not in conflict with the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | Uncertain | 2 | 6-33423572-C-A | 24 | 1.49e-5 | -5.840 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | -1.21 | Neutral | 0.140 | Benign | 0.184 | Benign | 3.91 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2047 | 0.4129 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||
| c.1648G>A | A550T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550T missense variant 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, Rosetta, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Foldetta, and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors (8/11) indicate a pathogenic impact, whereas only three suggest benign. Therefore, 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. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -10.555 | Likely Pathogenic | 0.621 | Likely Pathogenic | Likely Benign | 1.68 | Ambiguous | 0.3 | -0.05 | Likely Benign | 0.82 | Ambiguous | 0.73 | Ambiguous | 0.627 | Likely Pathogenic | -3.19 | Deleterious | 0.991 | Probably Damaging | 0.872 | Possibly Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.0931 | 0.4465 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1648G>C | A550P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A550P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -18.578 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.15 | Destabilizing | 0.3 | 6.75 | Destabilizing | 6.45 | Destabilizing | 0.67 | Ambiguous | 0.872 | Likely Pathogenic | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.971 | Probably Damaging | -1.32 | Pathogenic | 0.02 | Affected | 0.1476 | 0.3417 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1648G>T | A550S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550S missense variant is not reported in ClinVar (status: None) 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. FoldX, Rosetta, Foldetta, and premPS yield uncertain or inconclusive results and are therefore not considered evidence for either side. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for A550S. 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. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -12.166 | Likely Pathogenic | 0.569 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 1.08 | Ambiguous | 1.04 | Ambiguous | 0.80 | Ambiguous | 0.753 | Likely Pathogenic | -2.69 | Deleterious | 0.976 | Probably Damaging | 0.907 | Possibly Damaging | -1.29 | Pathogenic | 0.02 | Affected | 0.1739 | 0.3615 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1649C>G | A550G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550G missense variant 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 AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of reliable predictors indicate a pathogenic effect. 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 | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -15.086 | Likely Pathogenic | 0.776 | Likely Pathogenic | Likely Benign | 1.73 | Ambiguous | 0.0 | 1.82 | Ambiguous | 1.78 | Ambiguous | 0.85 | Ambiguous | 0.769 | Likely Pathogenic | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.932 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.1595 | 0.2758 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.164A>G | Q55R 2D AIThe SynGAP1 missense variant Q55R 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT 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 (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 both general and high‑accuracy predictors indicates that 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 | 0.332115 | Structured | 0.470108 | Uncertain | 0.461 | 0.657 | 0.000 | -6.626 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -1.15 | Neutral | 0.140 | Benign | 0.275 | Benign | 3.87 | Benign | 0.00 | Affected | 0.1607 | 0.1558 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.1657A>C | K553Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K553Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, and SIFT, whereas the majority of tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic; Rosetta is inconclusive and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all pathogenic) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence (10 pathogenic vs. 3 benign predictions) indicates that K553Q is most likely pathogenic, 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 | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -13.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.49 | Likely Benign | 1.01 | Destabilizing | 0.783 | Likely Pathogenic | -3.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.07 | Tolerated | 0.3477 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1660G>A | V554M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554M is not reported in ClinVar but is present in gnomAD (ID 6‑33438903‑G‑A). Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessment focuses on AlphaMissense‑Optimized, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. AlphaMissense‑Optimized predicts benign, the SGM Consensus is a tie and thus unavailable, and Foldetta is uncertain, so it is treated as unavailable. Overall, the available evidence leans toward a benign effect, and this does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | 6-33438903-G-A | 1 | 6.20e-7 | -8.118 | Likely Pathogenic | 0.671 | Likely Pathogenic | Likely Benign | -1.11 | Ambiguous | 0.0 | -0.20 | Likely Benign | -0.66 | Ambiguous | 0.73 | Ambiguous | 0.217 | Likely Benign | -2.26 | Neutral | 0.994 | Probably Damaging | 0.867 | Possibly Damaging | 3.22 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0743 | 0.2810 | 1 | 2 | -2.3 | 32.06 | |||||||||||||||||||||||||
| c.1667A>G | N556S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N556S (ClinVar ID 941099.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438910‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign effect. No other high‑accuracy or folding‑stability methods provide additional evidence. Overall, the majority of predictions support 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. | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | Uncertain | 1 | 6-33438910-A-G | 3 | 1.86e-6 | -6.576 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.14 | Likely Benign | 0.33 | Likely Benign | 0.16 | Likely Benign | 0.449 | Likely Benign | -3.60 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.22 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0.2641 | 0.3556 | 1 | 1 | 2.7 | -27.03 | 198.8 | 31.0 | 0.0 | 0.0 | -0.5 | 0.2 | X | Potentially Benign | Asn556 is located on the outer surface of an α-helix (res. Ala533-Val560). The carboxamide group of Asn556 forms hydrogen bonds with nearby residues such as Lys553 and Cys552. It also forms a hydrogen bond with the backbone carbonyl group of Cys552, which weakens the α-helix integrity. In the variant simulations, the hydroxyl group of Ser556 forms a more stable hydrogen bond with the backbone carbonyl oxygen of the same helix residue, Cys552, compared to Asn556 in the WT. Serine has a slightly lower propensity to reside in an α-helix than asparagine, which may exacerbate the negative effect on the α-helix integrity. However, the residue swap does not cause negative structural effects during the simulations. | ||||||||||||||
| c.1668C>A | N556K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, premPS, and SIFT, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict it to be pathogenic. 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 (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions support a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -10.017 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.10 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.12 | Likely Benign | 0.40 | Likely Benign | 0.510 | Likely Pathogenic | -4.48 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.08 | Pathogenic | 0.14 | Tolerated | 0.2024 | 0.2240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1668C>G | N556K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from FoldX, Rosetta, premPS, and SIFT; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation (i.e., no conflicting benign classification). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -10.017 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.10 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.12 | Likely Benign | 0.40 | Likely Benign | 0.510 | Likely Pathogenic | -4.48 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.08 | Pathogenic | 0.14 | Tolerated | 0.2024 | 0.2240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1669T>A | S557T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557T 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 premPS, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Predictions that are uncertain (AlphaMissense‑Default and Foldetta) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -9.089 | Likely Pathogenic | 0.418 | Ambiguous | Likely Benign | 2.14 | Destabilizing | 0.2 | 0.40 | Likely Benign | 1.27 | Ambiguous | 0.21 | Likely Benign | 0.744 | Likely Pathogenic | -2.53 | Deleterious | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.64 | Pathogenic | 0.07 | Tolerated | 0.1514 | 0.6336 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1669T>C | S557P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, 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 | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -15.383 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.91 | Destabilizing | 0.4 | 8.79 | Destabilizing | 7.85 | Destabilizing | 1.09 | Destabilizing | 0.934 | Likely Pathogenic | -4.60 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.76 | Pathogenic | 0.01 | Affected | 0.2222 | 0.6239 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1669T>G | S557A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Optimized and Rosetta, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus) predict a pathogenic impact. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Foldetta, and premPS. 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. 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 | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -11.044 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 1.26 | Ambiguous | 0.0 | 0.09 | Likely Benign | 0.68 | Ambiguous | 0.54 | Ambiguous | 0.801 | Likely Pathogenic | -2.70 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | -1.69 | Pathogenic | 0.05 | Affected | 0.4695 | 0.4836 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1672C>G | H558D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H558D 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; AlphaMissense‑Optimized and Foldetta are “Uncertain.” No evidence suggests a benign outcome. Consequently, the variant is most likely pathogenic based on the preponderance of predictions, and this assessment does not contradict the ClinVar status, which currently contains no entry for H558D. 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 | -14.948 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | 0.54 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.21 | Ambiguous | 1.03 | Destabilizing | 0.635 | Likely Pathogenic | -5.90 | Deleterious | 0.959 | Probably Damaging | 0.905 | Possibly Damaging | -1.26 | Pathogenic | 0.09 | Tolerated | 0.2233 | 0.0908 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1678G>C | V560L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V560L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from polyPhen‑2 HumDiv, ESM1b, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the bulk of evidence points to a benign effect, but the SGM Consensus and the presence of pathogenic signals from several high‑confidence tools introduce uncertainty. Thus, the variant is most likely benign based on the prevailing predictions, 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. | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | -10.191 | Likely Pathogenic | 0.533 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.0 | 0.48 | Likely Benign | 0.02 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -2.45 | Neutral | 0.508 | Possibly Damaging | 0.209 | Benign | -1.24 | Pathogenic | 0.40 | Tolerated | 3.37 | 35 | 0.1430 | 0.4162 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||
| c.1678G>T | V560L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V560L variant has no ClinVar entry (ClinVar status: None) but is catalogued in gnomAD (ID 6‑33440730‑G‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, ESM1b, and FATHMM (polyPhen‑2 HumVar is benign, AlphaMissense‑Default is uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning pathogenic (2 pathogenic vs 1 benign), and Foldetta indicating a benign stability change. Overall, the majority of conventional tools favor a benign classification, yet the high‑accuracy consensus and Foldetta suggest a pathogenic signal. Based on the most reliable 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. | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | 6-33440730-G-T | 1 | 6.34e-7 | -10.191 | Likely Pathogenic | 0.533 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.0 | 0.48 | Likely Benign | 0.02 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -2.45 | Neutral | 0.508 | Possibly Damaging | 0.209 | Benign | -1.24 | Pathogenic | 0.40 | Tolerated | 3.37 | 35 | 0.1430 | 0.4162 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1684C>G | P562A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P562A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: only premPS classifies it as benign, whereas REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity; Rosetta remains uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic change, 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. Consequently, the variant is most likely pathogenic. This assessment does not contradict ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022306 | Structured | 0.023606 | Uncertain | 0.893 | 0.200 | 0.000 | -13.554 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.87 | Destabilizing | 0.0 | 1.28 | Ambiguous | 2.08 | Destabilizing | 0.39 | Likely Benign | 0.633 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.59 | Pathogenic | 0.01 | Affected | 0.3418 | 0.2883 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1684C>T | P562S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P562S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The only tools with uncertain outcomes are Rosetta and premPS, which provide inconclusive results. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: 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. Consequently, the variant is most likely pathogenic based on the collective 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 | GAP | 0.022306 | Structured | 0.023606 | Uncertain | 0.893 | 0.200 | 0.000 | -14.293 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.1 | 1.59 | Ambiguous | 2.26 | Destabilizing | 0.70 | Ambiguous | 0.708 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.62 | Pathogenic | 0.01 | Affected | 0.3365 | 0.2900 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1690G>A | E564K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564K is not reported in ClinVar and is present in the gnomAD database (variant ID 6‑33440742‑G‑A). Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only SIFT predicts a benign outcome. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence supports 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 | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | 6-33440742-G-A | -15.834 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.1 | 2.06 | Destabilizing | 1.41 | Ambiguous | 0.89 | Ambiguous | 0.854 | Likely Pathogenic | -3.95 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | -1.35 | Pathogenic | 0.10 | Tolerated | 3.37 | 35 | 0.1988 | 0.5280 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||
| c.1696A>C | K566Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K566Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and Rosetta, whereas a majority of tools predict a pathogenic impact: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, premPS, PROVEAN, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Because the preponderance of evidence points to a deleterious effect, 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 | GAP | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | -11.475 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 1.48 | Ambiguous | 0.1 | -0.35 | Likely Benign | 0.57 | Ambiguous | 1.25 | Destabilizing | 0.762 | Likely Pathogenic | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.07 | Tolerated | 0.3824 | 0.1282 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.16G>C | A6P 2D AIThe SynGAP1 missense variant A6P 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 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 | 0.566480 | Disordered | 0.549054 | Binding | 0.377 | 0.920 | 0.875 | -3.440 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.148 | Likely Benign | -0.12 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.06 | Benign | 0.00 | Affected | 0.2093 | 0.5007 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.16G>T | A6S 2D AIThe SynGAP1 missense variant A6S is reported in gnomAD (variant ID 6-33420280‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: 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 and the high‑accuracy methods 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 | 0.566480 | Disordered | 0.549054 | Binding | 0.377 | 0.920 | 0.875 | 6-33420280-G-T | -2.485 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.06 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2720 | 0.5457 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.1702G>C | V568L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V568L variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and polyPhen‑2 HumVar, while those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain predictions come from Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools predict a pathogenic impact, 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. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | -9.503 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.30 | Likely Benign | 0.3 | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.56 | Ambiguous | 0.651 | Likely Pathogenic | -2.69 | Deleterious | 0.511 | Possibly Damaging | 0.147 | Benign | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.0944 | 0.3312 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||
| c.1702G>T | V568L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic effect, whereas three tools (FoldX, Foldetta, and polyPhen‑2 HumVar) predict a benign outcome; the remaining three (Rosetta, premPS, AlphaMissense‑Optimized) are inconclusive. 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 preponderance of evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | Uncertain | 1 | -9.503 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.30 | Likely Benign | 0.3 | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.56 | Ambiguous | 0.651 | Likely Pathogenic | -2.69 | Deleterious | 0.511 | Possibly Damaging | 0.147 | Benign | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.0944 | 0.3312 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1705T>A | F569I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569I is not listed in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as pathogenic. No predictor reports a benign outcome, so the benign group is empty. 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 indicates pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024393 | Structured | 0.054289 | Uncertain | 0.941 | 0.242 | 0.000 | -15.362 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.2 | 4.23 | Destabilizing | 3.99 | Destabilizing | 1.51 | Destabilizing | 0.903 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.1950 | 0.1973 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1708G>A | A570T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A570T is not reported in ClinVar and is absent from gnomAD. Prediction tools that provide a definitive call all indicate a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenicity. No tool reports a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain and therefore do not influence the overall assessment. High‑accuracy methods specifically show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Taken together, the majority of conclusive predictions support a pathogenic effect. Consequently, the variant is most likely pathogenic, and this conclusion 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 | GAP | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -11.390 | Likely Pathogenic | 0.801 | Likely Pathogenic | Ambiguous | 1.45 | Ambiguous | 0.3 | 1.67 | Ambiguous | 1.56 | Ambiguous | 0.86 | Ambiguous | 0.568 | Likely Pathogenic | -3.28 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.26 | Pathogenic | 0.05 | Affected | 0.1345 | 0.3874 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1708G>C | A570P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A570P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: 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 variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods corroborate this: 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. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this assessment 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 | GAP | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -15.178 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.21 | Destabilizing | 0.5 | 8.45 | Destabilizing | 6.83 | Destabilizing | 1.19 | Destabilizing | 0.832 | Likely Pathogenic | -4.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.31 | Pathogenic | 0.02 | Affected | 0.1965 | 0.2578 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1708G>T | A570S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A570S 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. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, and ESM1b) yield uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the majority of reliable predictions indicate 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 | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -7.893 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.77 | Ambiguous | 0.1 | 1.68 | Ambiguous | 1.23 | Ambiguous | 0.51 | Ambiguous | 0.399 | Likely Benign | -2.26 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.19 | Pathogenic | 0.17 | Tolerated | 0.2091 | 0.3256 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1709C>G | A570G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A570G 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 SIFT and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The remaining tools (FoldX, premPS, ESM1b, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta are unavailable due to mixed or uncertain outputs. Overall, the majority of evaluated tools (seven pathogenic vs. two benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -7.509 | In-Between | 0.562 | Ambiguous | Likely Benign | 1.34 | Ambiguous | 0.1 | 2.12 | Destabilizing | 1.73 | Ambiguous | 0.99 | Ambiguous | 0.607 | Likely Pathogenic | -3.62 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.30 | Pathogenic | 0.09 | Tolerated | 0.1700 | 0.2499 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1711T>A | S571T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S571T 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, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM; AlphaMissense‑Default remains uncertain. 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 (seven) predict pathogenicity, while six predict benignity, and the high‑accuracy subset is split. Thus, the variant is most likely pathogenic based on the prevailing 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 | GAP | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | -8.243 | Likely Pathogenic | 0.431 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | -0.21 | Likely Benign | 0.08 | Likely Benign | 0.25 | Likely Benign | 0.564 | Likely Pathogenic | -2.76 | Deleterious | 0.933 | Possibly Damaging | 0.933 | Probably Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.1360 | 0.4014 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1711T>C | S571P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S571P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Consequently, the aggregate evidence strongly supports a pathogenic effect for S571P, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | Uncertain | 1 | -14.701 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.18 | Destabilizing | 0.2 | 4.89 | Destabilizing | 4.04 | Destabilizing | 0.87 | Ambiguous | 0.814 | Likely Pathogenic | -4.68 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.02 | Affected | 0.2195 | 0.3760 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1711T>G | S571A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S571A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑2 split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, and the SGM Consensus remains unavailable. Overall, the preponderance of evidence points to a benign impact for S571A, 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 | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | -6.344 | Likely Benign | 0.233 | Likely Benign | Likely Benign | -0.44 | Likely Benign | 0.1 | -0.19 | Likely Benign | -0.32 | Likely Benign | 0.51 | Ambiguous | 0.563 | Likely Pathogenic | -2.69 | Deleterious | 0.980 | Probably Damaging | 0.994 | Probably Damaging | -1.22 | Pathogenic | 0.09 | Tolerated | 0.4739 | 0.2671 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||
| c.1718G>A | R573Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R573Q is reported in ClinVar as Pathogenic (ClinVar ID 1176819.0) and is not present in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Two tools give inconclusive results: Rosetta (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.032433 | Uncertain | 0.934 | 0.235 | 0.000 | Likely Pathogenic | 1 | -9.900 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 2.28 | Destabilizing | 0.8 | 1.94 | Ambiguous | 2.11 | Destabilizing | 1.08 | Destabilizing | 0.733 | Likely Pathogenic | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.12 | Tolerated | 3.37 | 35 | 0.2390 | 0.1651 | 1 | 1 | 1.0 | -28.06 | 230.1 | 49.9 | 0.0 | 0.0 | -0.6 | 0.0 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, although the carboxamide group of the Gln573 side chain can hydrogen bond with the carboxylate group of Glu582 or the hydroxyl group of Ser668, these interactions are not as coordinated, stable, or strong as those of the positively charged Arg573. Consequently, the integrity of the opposing α-helix end (res. Glu582-Met603) is weakened. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | |||||||||||||||
| c.1729G>A | A577T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A577T is listed in ClinVar as benign (ClinVar ID 2195056.0) and is present in gnomAD (ID 6‑33440781‑G‑A). 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other high‑confidence stability predictions are available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, which aligns 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 | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | Benign | 1 | 6-33440781-G-A | 6 | 3.72e-6 | -5.311 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.70 | Ambiguous | 0.54 | Ambiguous | 0.427 | Likely Benign | -1.47 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.47 | Tolerated | 3.37 | 34 | 0.1657 | 0.5875 | 1 | 0 | -2.5 | 30.03 | 191.9 | -43.4 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. In the variant simulations, the hydroxyl group of the Thr577 side chain hydrogen bonds with the backbone atoms of Arg573 and Lys574 within the same helix, which has the potential to weaken the stability of the secondary structure element. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | |||||||||||||
| c.1729G>C | A577P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only SIFT, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; premPS is inconclusive and is therefore not counted. High‑accuracy assessments further support a deleterious impact: 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 predicts pathogenic. Based on the consensus of these predictions, 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 | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -9.009 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.93 | Destabilizing | 0.2 | 9.88 | Destabilizing | 6.91 | Destabilizing | 0.87 | Ambiguous | 0.585 | Likely Pathogenic | -2.72 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.20 | Tolerated | 0.2256 | 0.4600 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1729G>T | A577S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577S 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 this is consistent with the absence 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 Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -4.417 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.60 | Ambiguous | 0.35 | Likely Benign | 0.05 | Likely Benign | 0.342 | Likely Benign | -0.30 | Neutral | 0.981 | Probably Damaging | 0.992 | Probably Damaging | -1.24 | Pathogenic | 0.80 | Tolerated | 0.2763 | 0.5056 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.172A>G | M58V 2D AIThe SynGAP1 missense variant M58V is listed in ClinVar (ID 2962156.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized, SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta (protein‑folding stability) is available only for the first two; Foldetta data are missing. The SGM Consensus, based on a majority of benign predictions, indicates a likely benign outcome. Overall, the majority of evidence points 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 | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | Uncertain | 1 | -2.211 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | -0.71 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2951 | 0.3917 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||
| c.1730C>G | A577G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577G is listed in ClinVar as Benign (ClinVar ID 1010280.0) and is present in gnomAD (ID 6‑33440782‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, 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 FATHMM. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy methods give a benign verdict: AlphaMissense‑Optimized is benign, the SGM‑Consensus is Likely Benign, and Foldetta is uncertain. Overall, the majority of reliable predictions support a benign impact, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | Benign/Likely benign | 2 | 6-33440782-C-G | 1 | 6.20e-7 | -5.717 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.0 | 1.02 | Ambiguous | 0.93 | Ambiguous | 0.86 | Ambiguous | 0.443 | Likely Benign | -1.84 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.31 | Pathogenic | 0.31 | Tolerated | 3.37 | 34 | 0.2120 | 0.3780 | 1 | 0 | -2.2 | -14.03 | 158.7 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. The introduced residue, glycine, is known as an “α-helix breaker.” However, the residue swap caused only minor helix shortening in one of the replica simulations for the variant system. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | |||||||||||||
| c.1736G>A | R579Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R579Q is listed in ClinVar with an uncertain significance (ClinVar ID 3964539) and is present in gnomAD (6‑33440788‑G‑A). Prediction tools that indicate a benign effect include SIFT and AlphaMissense‑Optimized, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Therefore, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.022872 | Uncertain | 0.877 | 0.244 | 0.000 | Uncertain | 2 | 6-33440788-G-A | 18 | 1.12e-5 | -9.193 | Likely Pathogenic | 0.690 | Likely Pathogenic | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.68 | Ambiguous | 1.13 | Destabilizing | 0.673 | Likely Pathogenic | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.34 | Pathogenic | 0.06 | Tolerated | 3.37 | 34 | 0.2677 | 0.1334 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.1738G>A | G580S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580S is listed in ClinVar with an “Uncertain” status (ClinVar ID 1487029.0) and is present in the gnomAD database (gnomAD ID 6‑33440790‑G‑A). Among the available in‑silico predictors, the majority (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic effect, whereas only SIFT predicts a benign outcome. Predictions that are inconclusive or uncertain include Rosetta, Foldetta, premPS, AlphaMissense‑Optimized, and the SGM‑Consensus (which is derived from the pathogenic majority of the four contributing tools). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain (combining a pathogenic FoldX result with an uncertain Rosetta result). Overall, the preponderance of evidence points to a pathogenic effect, which is in contrast to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | Uncertain | 1 | 6-33440790-G-A | 1 | 6.20e-7 | -10.788 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 2.84 | Destabilizing | 0.2 | 0.59 | Ambiguous | 1.72 | Ambiguous | 0.87 | Ambiguous | 0.644 | Likely Pathogenic | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.23 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | 0.2509 | 0.3085 | 1 | 0 | -0.4 | 30.03 | 233.9 | -49.3 | 0.8 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | Gly580 is located on the outer surface in a short α-α loop turn connecting two α-helices (res. Arg563-Glu578, res. Glu582-Phe608) in the WT simulations. In the variant simulations, the side chain of Ser580 faces outward, and its hydroxyl group does not make any new or additional interactions compared to Gly580 in the WT simulations that could affect the protein structure. | |||||||||||||
| c.1739G>A | G580D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580D is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while premPS and Rosetta are uncertain. High‑accuracy tools reinforce this assessment: 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 predicts pathogenic. No benign predictions are present. 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 | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -10.086 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 2.85 | Destabilizing | 0.1 | 1.39 | Ambiguous | 2.12 | Destabilizing | 0.83 | Ambiguous | 0.712 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.25 | Pathogenic | 0.04 | Affected | 0.1793 | 0.1971 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1739G>C | G580A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580A is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity are unanimous: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus all predict a deleterious effect. Tools with uncertain or inconclusive results (Rosetta and premPS) are noted as unavailable for pathogenicity inference. 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, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, also classifies the variant as Pathogenic. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, 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 | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -10.841 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 0.1 | 1.55 | Ambiguous | 2.20 | Destabilizing | 0.64 | Ambiguous | 0.646 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.22 | Pathogenic | 0.05 | Affected | 0.3657 | 0.2862 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1742G>A | R581Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R581Q is reported in ClinVar as benign (ClinVar ID 1388591.0) and is present in gnomAD (ID 6‑33440794‑G‑A). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as benign. No other high‑confidence stability predictions are available. Overall, the predictions are mixed, with a slight bias toward benign outcomes from the majority of tools and the high‑accuracy AlphaMissense‑Optimized and Foldetta results. Therefore, the variant is most likely benign based on the current computational evidence, which is consistent with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.029544 | Uncertain | 0.829 | 0.236 | 0.000 | Benign | 1 | 6-33440794-G-A | 8 | 4.96e-6 | -7.584 | In-Between | 0.673 | Likely Pathogenic | Likely Benign | 1.31 | Ambiguous | 0.1 | -0.42 | Likely Benign | 0.45 | Likely Benign | 0.88 | Ambiguous | 0.481 | Likely Benign | -2.77 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.21 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.2742 | 0.1851 | 1 | 1 | 1.0 | -28.06 | 239.6 | 53.5 | -0.2 | 0.2 | -0.4 | 0.1 | X | Potentially Pathogenic | Arg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 on a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral carboxamide group of the Gln581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 or forms hydrogen bonds sporadically with nearby residues (e.g., Asp583, Arg587). Thus, although no drastic changes are observed in the variant simulations, the residue swap could weaken the tertiary structure assembly. | |||||||||||||
| c.1747G>A | D583N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D583N is reported in gnomAD (ID 6‑33440799‑G‑A) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy assessment indicates AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the predictions are split, with a slight tilt toward pathogenicity from the consensus and high‑accuracy tools, while stability‑based methods suggest benign. Therefore, the variant is most likely pathogenic based on the aggregate predictions, 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 | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | 6-33440799-G-A | 3 | 1.86e-6 | -8.048 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 0.13 | Likely Benign | 0.1 | 0.00 | Likely Benign | 0.07 | Likely Benign | 0.21 | Likely Benign | 0.632 | Likely Pathogenic | -4.78 | Deleterious | 0.996 | Probably Damaging | 0.995 | Probably Damaging | -1.40 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 0.1024 | 0.3884 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.1747G>C | D583H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D583H is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, 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. FoldX and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available 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 | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -9.191 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | -0.07 | Likely Benign | 0.58 | Ambiguous | -0.22 | Likely Benign | 0.713 | Likely Pathogenic | -6.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 0.1217 | 0.4182 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1748A>G | D583G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583G missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and ESM1b, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—classify it as pathogenic. Uncertain results come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessment shows the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and AlphaMissense‑Optimized remains inconclusive; Foldetta also reports no definitive stability change. Overall, the preponderance of evidence points to a pathogenic effect for D583G, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -6.765 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 1.10 | Ambiguous | 0.2 | 0.56 | Ambiguous | 0.83 | Ambiguous | 0.10 | Likely Benign | 0.850 | Likely Pathogenic | -6.77 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 0.3072 | 0.4284 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.174G>A | M58I 2D AIThe SynGAP1 missense variant M58I is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33423583‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status. Thus, based on the available evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | 6-33423583-G-A | 1 | 6.20e-7 | -2.153 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | -0.55 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1397 | 0.3848 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.174G>C | M58I 2D AIThe SynGAP1 missense variant M58I 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are 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) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -2.153 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | -0.55 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1397 | 0.3848 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.174G>T | M58I 2D AIThe SynGAP1 missense variant M58I 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are 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, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions (seven benign vs. three pathogenic) suggest the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -2.153 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | -0.55 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1397 | 0.3848 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| 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.1753G>C | A585P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A585P is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic outcome. Based on the convergence of these predictions, 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 | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -10.999 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 5.44 | Destabilizing | 0.1 | 5.92 | Destabilizing | 5.68 | Destabilizing | 0.77 | Ambiguous | 0.549 | Likely Pathogenic | -3.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.33 | Pathogenic | 0.16 | Tolerated | 0.1884 | 0.2943 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1753G>T | A585S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A585S is not reported in ClinVar (no entry) and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts Likely Benign, while Foldetta remains uncertain. Overall, the majority of evidence supports a benign classification, 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 Benign | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -6.332 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.91 | Ambiguous | 0.2 | 1.44 | Ambiguous | 1.18 | Ambiguous | 0.02 | Likely Benign | 0.326 | Likely Benign | 0.39 | Neutral | 0.993 | Probably Damaging | 0.996 | Probably Damaging | -1.27 | Pathogenic | 0.98 | Tolerated | 0.2121 | 0.3388 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1754C>G | A585G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A585G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta reports an uncertain stability change. No evidence from these high‑confidence tools supports pathogenicity. Overall, the balance of evidence favors a benign effect for A585G, 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. | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -3.879 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 1.62 | Ambiguous | 0.0 | 1.94 | Ambiguous | 1.78 | Ambiguous | 0.59 | Ambiguous | 0.384 | Likely Benign | -1.16 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.33 | Pathogenic | 0.24 | Tolerated | 0.1724 | 0.2299 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1756G>C | D586H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586H missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from premPS and SIFT, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all indicate pathogenicity. The high‑accuracy methods reinforce this trend: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, as there is no conflicting status to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -10.104 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.3 | 0.89 | Ambiguous | 0.95 | Ambiguous | 0.26 | Likely Benign | 0.672 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.23 | Pathogenic | 0.17 | Tolerated | 0.1307 | 0.5558 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1757A>G | D586G 2D 3DClick to see structure in 3D Viewer AISynGAP1 D586G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that 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 | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -8.497 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 1.37 | Ambiguous | 0.3 | 2.49 | Destabilizing | 1.93 | Ambiguous | 0.34 | Likely Benign | 0.833 | Likely Pathogenic | -4.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 0.3334 | 0.5052 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1765A>T | I589F 2D AIThe SynGAP1 missense variant I589F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: 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, indicates a pathogenic impact. All available predictions are concordant and supportive. Therefore, the variant is most likely pathogenic based on current computational evidence, 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 Pathogenic | GAP | 0.018415 | Structured | 0.084536 | Uncertain | 0.927 | 0.214 | 0.000 | -15.300 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 7.38 | Destabilizing | 3.4 | 2.05 | Destabilizing | 4.72 | Destabilizing | 1.04 | Destabilizing | 0.905 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.98 | Pathogenic | 0.00 | Affected | 0.0888 | 0.2574 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1768A>G | S590G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S590G is listed in ClinVar (ID 1721675.0) with an uncertain significance status and is present in gnomAD (6‑33440820‑A‑G). Functional prediction tools that report a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive, as are FoldX, Rosetta, and premPS. Overall, the majority of evidence points toward a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | Conflicting | 2 | 6-33440820-A-G | 14 | 8.67e-6 | -14.277 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.67 | Ambiguous | 0.1 | 1.28 | Ambiguous | 0.98 | Ambiguous | 0.71 | Ambiguous | 0.379 | Likely Benign | -3.92 | Deleterious | 1.000 | Probably Damaging | 0.922 | Probably Damaging | 3.42 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.2627 | 0.4118 | 1 | 0 | 0.4 | -30.03 | 186.7 | 49.4 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | In the WT simulations, the hydroxyl group of Ser590, located on an α helix (res. Glu582-Met603), forms hydrogen bonds with the backbone carbonyl of Ala634 and/or the carboxamide group of the Asn635 side chain at the end of the opposing α helix (res. Thr619-Ala634).The residue swap could weaken the integrity of the α helix, as glycine is known as an “α helix breaker.” However, no discernible difference was observed between the WT and variant simulations in this regard. Importantly, Gly590 cannot form hydrogen bonds with the opposing helix in the same way that serine can, which could weaken the tertiary structure assembly between the two helices. | |||||||||||||
| c.1769G>A | S590N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590N is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) indicate a pathogenic or likely pathogenic impact. FoldX and Foldetta, which assess protein‑folding stability, return uncertain results and are therefore not considered evidence for either outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of pathogenic predictions strongly suggests that S590N is most likely pathogenic, a conclusion that is consistent with the absence of ClinVar annotation and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -15.149 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.1 | 2.10 | Destabilizing | 1.69 | Ambiguous | 1.48 | Destabilizing | 0.411 | Likely Benign | -2.96 | Deleterious | 0.921 | Possibly Damaging | 0.598 | Possibly Damaging | 3.14 | Benign | 0.01 | Affected | 0.1254 | 0.4202 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1769G>C | S590T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590T 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. Two tools (premPS and AlphaMissense‑Default) return 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 (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to 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 | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -12.472 | Likely Pathogenic | 0.458 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.33 | Likely Benign | 0.64 | Ambiguous | 0.459 | Likely Benign | -2.89 | Deleterious | 0.183 | Benign | 0.050 | Benign | 3.15 | Benign | 0.08 | Tolerated | 0.1420 | 0.5723 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1771G>A | A591T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591T is listed in ClinVar with an uncertain significance designation and is observed in gnomAD (variant ID 6‑33440823‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability metrics are available. Overall, the balance of evidence favors a pathogenic interpretation, 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 | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | Conflicting | 3 | 6-33440823-G-A | 18 | 1.12e-5 | -9.572 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 1.61 | Ambiguous | 0.2 | 1.00 | Ambiguous | 1.31 | Ambiguous | 1.19 | Destabilizing | 0.270 | Likely Benign | -3.40 | Deleterious | 0.955 | Possibly Damaging | 0.209 | Benign | 3.48 | Benign | 0.01 | Affected | 3.37 | 35 | 0.1225 | 0.4155 | 1 | 0 | -2.5 | 30.03 | 202.9 | -43.4 | 0.2 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | 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, the hydroxyl group of Thr591 can form hydrogen bonds with the backbone carbonyl of Ile843 in the opposing loop or the backbone carbonyl group of Arg587. These interactions could either reinforce the tertiary assembly or weaken the α helix unity. Additionally, the Thr591 side chain can hydrogen bond with the guanidinium group of the Arg587 side chain, potentially strengthening the α helix unity.Overall, the residue swap does not seem to cause any major negative effects on the protein structure. | |||||||||||||
| 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.1771G>T | A591S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts 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 a likely benign effect, and the Foldetta stability analysis is inconclusive (unavailable). Consequently, the variant is most likely benign 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 Benign | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | -7.535 | In-Between | 0.126 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.1 | 1.21 | Ambiguous | 0.90 | Ambiguous | 0.49 | Likely Benign | 0.083 | Likely Benign | -2.11 | Neutral | 0.034 | Benign | 0.082 | Benign | 3.52 | Benign | 0.19 | Tolerated | 0.2405 | 0.3304 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1772C>G | A591G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only PROVEAN predicts a pathogenic outcome. 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. Overall, the majority of evidence points to a benign impact for A591G, 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 | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | -6.596 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.2 | 1.74 | Ambiguous | 1.48 | Ambiguous | 0.83 | Ambiguous | 0.142 | Likely Benign | -2.77 | Deleterious | 0.007 | Benign | 0.009 | Benign | 3.60 | Benign | 0.16 | Tolerated | 0.2117 | 0.2228 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1774T>A | S592T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S592T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include Foldetta, SIFT, and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a unanimous pathogenic vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity; Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, also reports a benign effect. Predictions from FoldX, Rosetta, and premPS are inconclusive and are treated as unavailable. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S592T, 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 | GAP | 0.012270 | Structured | 0.100070 | Uncertain | 0.913 | 0.182 | 0.000 | -11.670 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.86 | Ambiguous | 0.1 | -0.88 | Ambiguous | -0.01 | Likely Benign | 0.61 | Ambiguous | 0.819 | Likely Pathogenic | -2.79 | Deleterious | 0.933 | Possibly Damaging | 0.933 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 0.1531 | 0.4684 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1774T>C | S592P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S592P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are inconclusive or missing. Based on the overwhelming agreement among pathogenic predictors and the absence of benign evidence, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.012270 | Structured | 0.100070 | Uncertain | 0.913 | 0.182 | 0.000 | -14.621 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.26 | Destabilizing | 0.1 | 2.36 | Destabilizing | 3.31 | Destabilizing | 1.24 | Destabilizing | 0.909 | Likely Pathogenic | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.11 | Tolerated | 0.2412 | 0.4259 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1774T>G | S592A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S592A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, SIFT, and AlphaMissense‑Optimized, whereas a majority (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. 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 balance of evidence favors a pathogenic classification. This conclusion is not contradicted by 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 | GAP | 0.012270 | Structured | 0.100070 | Uncertain | 0.913 | 0.182 | 0.000 | -10.902 | Likely Pathogenic | 0.572 | Likely Pathogenic | Likely Benign | -0.48 | Likely Benign | 0.1 | -0.93 | Ambiguous | -0.71 | Ambiguous | 0.79 | Ambiguous | 0.661 | Likely Pathogenic | -2.72 | Deleterious | 0.980 | Probably Damaging | 0.994 | Probably Damaging | -1.25 | Pathogenic | 0.44 | Tolerated | 0.4878 | 0.3318 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1780T>A | F594I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594I is not reported in ClinVar and has no entries in gnomAD. In silico assessment shows that all evaluated pathogenicity predictors—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—classify the substitution as pathogenic, while FoldX, Rosetta, and Foldetta provide inconclusive results. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Consequently, the overwhelming majority of predictions point to a pathogenic impact. The variant is therefore most likely pathogenic, and 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 | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -11.271 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.93 | Ambiguous | 0.1 | 1.67 | Ambiguous | 1.80 | Ambiguous | 1.61 | Destabilizing | 0.935 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.91 | Pathogenic | 0.02 | Affected | 0.1694 | 0.1925 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1789T>A | F597I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: 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) predicts pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -13.674 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.62 | Destabilizing | 0.9 | 2.15 | Destabilizing | 2.89 | Destabilizing | 1.45 | Destabilizing | 0.951 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -2.18 | Pathogenic | 0.01 | Affected | 0.2008 | 0.1815 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.178G>C | D60H 2D AIThe SynGAP1 missense variant D60H 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 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 leans toward a benign interpretation, with no ClinVar entry to contradict this assessment. 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 | -5.257 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -1.59 | Neutral | 0.972 | Probably Damaging | 0.969 | Probably Damaging | 3.91 | Benign | 0.00 | Affected | 0.1433 | 0.8401 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.1798C>G | P600A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from Rosetta and premPS, while the remaining 11 tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain result. Taken together, the overwhelming majority of evidence indicates that P600A 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 | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -11.385 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.0 | -3.30 | Stabilizing | -0.57 | Ambiguous | 0.39 | Likely Benign | 0.581 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.38 | Pathogenic | 0.03 | Affected | 0.3692 | 0.4132 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1798C>T | P600S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of other in‑silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. No contradictory evidence exists in ClinVar. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -12.002 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.54 | Destabilizing | 0.1 | -2.60 | Stabilizing | -0.03 | Likely Benign | 0.52 | Ambiguous | 0.717 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.40 | Pathogenic | 0.01 | Affected | 0.3744 | 0.4200 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| 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.17C>G | A6G 2D AIThe SynGAP1 missense variant A6G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 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 | 0.566480 | Disordered | 0.549054 | Binding | 0.377 | 0.920 | 0.875 | -2.786 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.31 | Neutral | 0.052 | Benign | 0.004 | Benign | 4.08 | Benign | 0.00 | Affected | 0.2139 | 0.4369 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1801G>A | A601T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601T 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 are FATHMM and AlphaMissense‑Optimized, whereas the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently flag the variant as deleterious. Two tools, FoldX and premPS, return uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence indicates that 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. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -10.635 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 1.55 | Ambiguous | 0.1 | 2.66 | Destabilizing | 2.11 | Destabilizing | 0.76 | Ambiguous | 0.642 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.57 | Benign | 0.00 | Affected | 0.1564 | 0.5554 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1801G>C | A601P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601P 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, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all report pathogenicity. No prediction or stability result 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 | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -14.584 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.90 | Destabilizing | 0.6 | 8.84 | Destabilizing | 6.87 | Destabilizing | 0.87 | Ambiguous | 0.713 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2176 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1801G>T | A601S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601S 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 agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yields an uncertain result. Overall, more tools (six) 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. | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -11.248 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.21 | Ambiguous | 0.79 | Ambiguous | 0.541 | Likely Pathogenic | -2.99 | Deleterious | 0.983 | Probably Damaging | 0.993 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2732 | 0.4730 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1804A>T | I602F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome. Predictions that are uncertain or inconclusive are Rosetta, 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 as Uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Therefore, 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 | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -13.974 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 1.1 | -0.61 | Ambiguous | 0.93 | Ambiguous | 0.87 | Ambiguous | 0.822 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.937 | Probably Damaging | -1.82 | Pathogenic | 0.00 | Affected | 0.0708 | 0.2343 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1810T>A | S604T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive (FoldX, Rosetta, AlphaMissense‑Optimized) are treated as unavailable. 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 (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall pattern 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. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -9.674 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.64 | Ambiguous | 0.1 | -0.58 | Ambiguous | 0.03 | Likely Benign | -0.16 | Likely Benign | 0.337 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | 3.19 | Benign | 0.08 | Tolerated | 0.1687 | 0.4919 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1810T>C | S604P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification for S604P, 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 | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.953 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.76 | Destabilizing | 0.3 | 8.40 | Destabilizing | 6.08 | Destabilizing | 0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.2524 | 0.4829 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1810T>G | S604A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604A has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to a consensus. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With two of the three high‑accuracy tools indicating benign and no ClinVar evidence to contradict, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.017 | Likely Pathogenic | 0.608 | Likely Pathogenic | Likely Benign | 0.02 | Likely Benign | 0.1 | -0.60 | Ambiguous | -0.29 | Likely Benign | 0.11 | Likely Benign | 0.378 | Likely Benign | -2.99 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | 3.25 | Benign | 0.08 | Tolerated | 0.5198 | 0.3530 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.1813C>G | P605A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -10.085 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.58 | Destabilizing | 0.3 | 2.42 | Destabilizing | 2.50 | Destabilizing | 0.91 | Ambiguous | 0.744 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.75 | Pathogenic | 0.00 | Affected | 0.3432 | 0.4607 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1813C>T | P605S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | Uncertain | 1 | -10.830 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 3.34 | Destabilizing | 3.37 | Destabilizing | 1.00 | Destabilizing | 0.718 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.70 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3397 | 0.4676 | 1 | -1 | 0.8 | -10.04 | 213.8 | -15.4 | -0.3 | 0.2 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the hydroxyl side chain of Ser605 forms hydrogen bonds with the backbone carbonyl groups of Ala601 and Ile602. Importantly, the helix end is more stable than with Pro605 in the WT. Indeed, proline is a more effective secondary structure breaker compared to serine.Thus, the residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest. Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | |||||||||||||||
| c.1816A>G | S606G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S606G is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is treated as unavailable. Overall, the majority 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 | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.281 | Likely Pathogenic | 0.603 | Likely Pathogenic | Likely Benign | 0.43 | Likely Benign | 0.1 | 1.42 | Ambiguous | 0.93 | Ambiguous | 0.84 | Ambiguous | 0.229 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.35 | Benign | 0.04 | Affected | 0.2286 | 0.3279 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1817G>A | S606N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S606N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Because the majority of individual predictors lean toward pathogenic and the SGM‑Consensus, a high‑confidence consensus, also indicates pathogenicity, the variant is most likely pathogenic. This conclusion 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 Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.352 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.11 | Likely Benign | 0.1 | 0.20 | Likely Benign | 0.16 | Likely Benign | 0.76 | Ambiguous | 0.136 | Likely Benign | -2.99 | Deleterious | 0.920 | Possibly Damaging | 0.955 | Probably Damaging | 3.37 | Benign | 0.10 | Tolerated | 0.1137 | 0.3218 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1817G>C | S606T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606T 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, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results 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 (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools predict pathogenicity, and the SGM Consensus supports this view, while the high‑accuracy methods give mixed results. Thus, 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. | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.052 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.06 | Likely Benign | 0.1 | -0.91 | Ambiguous | -0.43 | Likely Benign | 0.57 | Ambiguous | 0.203 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.933 | Probably Damaging | 3.34 | Benign | 0.03 | Affected | 0.1260 | 0.4513 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1822T>A | F608I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenic or likely pathogenic. The only tool with an inconclusive result is FoldX, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -14.939 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.92 | Ambiguous | 0.1 | 2.14 | Destabilizing | 2.03 | Destabilizing | 1.24 | Destabilizing | 0.904 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.62 | Pathogenic | 0.00 | Affected | 0.2115 | 0.2361 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1826G>C | G609A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609A 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, PROVEAN, and FATHMM. One tool, Foldetta, yields an uncertain result. 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‑to‑2 split, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -6.790 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 2.38 | Destabilizing | 0.3 | 0.01 | Likely Benign | 1.20 | Ambiguous | 0.43 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.282 | Benign | 0.164 | Benign | -1.43 | Pathogenic | 0.10 | Tolerated | 0.3812 | 0.3896 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1828C>G | L610V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L610V is reported in gnomAD (ID 6‑33440880‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, while only AlphaMissense‑Optimized predicts a benign outcome. 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 this view: AlphaMissense‑Optimized indicates benign, whereas the SGM Consensus remains pathogenic and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. With the overwhelming majority of tools predicting pathogenicity and no ClinVar evidence 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 | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | 6-33440880-C-G | 3 | 1.86e-6 | -11.304 | Likely Pathogenic | 0.474 | Ambiguous | Likely Benign | 2.24 | Destabilizing | 0.3 | 0.76 | Ambiguous | 1.50 | Ambiguous | 1.21 | Destabilizing | 0.740 | Likely Pathogenic | -2.86 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.46 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1515 | 0.3039 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1833G>A | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is reported in gnomAD (ID 6‑33440885‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized classifies it as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain stability change. No folding‑stability method provides definitive evidence. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with ClinVar status, which lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | 6-33440885-G-A | 1 | 6.19e-7 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | 0.292 | Likely Benign | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 0.1009 | 0.2302 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||
| c.1833G>C | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points toward a pathogenic classification, 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | 0.292 | Likely Benign | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 0.1009 | 0.2302 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1833G>T | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Predictors that classify it as pathogenic are SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, premPS, and Foldetta) provide uncertain or unavailable results. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic; Foldetta’s stability output is unavailable. Overall, the majority of predictions lean toward a benign effect, 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. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | 0.292 | Likely Benign | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 0.1009 | 0.2302 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1834C>A | Q612K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612K is not reported in ClinVar (ClinVar status: not listed) and has no entry in gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and SIFT, whereas pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; premPS and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, 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 tools predict pathogenicity, and the high‑accuracy consensus also leans pathogenic, while the folding‑stability method suggests benign. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -12.393 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.32 | Likely Benign | 0.81 | Ambiguous | 0.619 | Likely Pathogenic | -3.88 | Deleterious | 0.931 | Possibly Damaging | 0.931 | Probably Damaging | -1.22 | Pathogenic | 0.19 | Tolerated | 0.1810 | 0.3641 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1835A>G | Q612R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612R 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 SIFT and FoldX. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta are uncertain. No high‑accuracy tool provides a benign prediction. Overall, the majority of available evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -10.571 | Likely Pathogenic | 0.837 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.2 | 1.56 | Ambiguous | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.683 | Likely Pathogenic | -3.85 | Deleterious | 0.956 | Probably Damaging | 0.969 | Probably Damaging | -1.29 | Pathogenic | 0.10 | Tolerated | 0.1480 | 0.2196 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1843C>G | P615A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P615A variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include SIFT and Rosetta, whereas the majority of predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all suggest a pathogenic impact. Uncertain results are reported by FoldX, Foldetta, and premPS. 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’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P615A, 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 | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.156 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 1.73 | Ambiguous | 0.3 | 0.35 | Likely Benign | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.693 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.3169 | 0.3214 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1843C>T | P615S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615S is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a pathogenic effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM Consensus also indicates a likely pathogenic outcome. No tools predict a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta’s stability prediction is uncertain and therefore not taken as evidence. Overall, the preponderance of evidence points to the variant being most likely pathogenic, with no contradiction to the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.566 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.87 | Ambiguous | 0.98 | Ambiguous | 0.780 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.19 | Pathogenic | 0.04 | Affected | 0.3191 | 0.3310 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1846G>C | D616H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616H 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 REVEL, premPS, and FATHMM. Those that agree on a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results—Rosetta and AlphaMissense‑Optimized—so their outputs are treated as unavailable for inference. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is Pathogenic. Overall, the majority of evidence points to a pathogenic effect. The variant’s predicted pathogenicity does not contradict ClinVar status, as no ClinVar classification exists. 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 | -9.815 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 2.13 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.01 | Destabilizing | 0.45 | Likely Benign | 0.316 | Likely Benign | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.952 | Probably Damaging | 3.30 | Benign | 0.03 | Affected | 0.1330 | 0.4273 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| 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.1849G>A | E617K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617K is not reported in ClinVar but is present in gnomAD (6‑33440901‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. A third set of methods (Foldetta, AlphaMissense‑Optimized, Rosetta) yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect for E617K, 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | 6-33440901-G-A | 1 | 6.20e-7 | -10.702 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.37 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.78 | Ambiguous | 0.17 | Likely Benign | 0.534 | Likely Pathogenic | -3.32 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | -1.34 | Pathogenic | 0.48 | Tolerated | 3.37 | 35 | 0.1981 | 0.6282 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.184G>A | D62N 2D AIThe SynGAP1 missense variant D62N is reported in gnomAD (variant ID 6‑33423593‑G‑A) but has no ClinVar entry. In silico prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools indicates that D62N is most likely benign, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | 6-33423593-G-A | 1 | 6.20e-7 | -4.607 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.08 | Neutral | 0.028 | Benign | 0.032 | Benign | 4.11 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1670 | 0.6154 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.184G>C | D62H 2D AIThe SynGAP1 missense variant D62H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, D62H 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -5.253 | Likely Benign | 0.511 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -1.53 | Neutral | 0.172 | Benign | 0.248 | Benign | 4.05 | Benign | 0.00 | Affected | 0.2059 | 0.6579 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.1852C>A | Q618K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618K is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33440904‑C‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b is uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign result; and Foldetta also predicts benign stability. No predictions or folding stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, 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. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | 6-33440904-C-A | 24 | 1.49e-5 | -7.708 | In-Between | 0.229 | Likely Benign | Likely Benign | 0.02 | Likely Benign | 0.0 | 0.16 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | 0.281 | Likely Benign | -0.05 | Neutral | 0.338 | Benign | 0.111 | Benign | -1.21 | Pathogenic | 0.29 | Tolerated | 3.37 | 35 | 0.1413 | 0.2750 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.1853A>G | Q618R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618R 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, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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 | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -2.513 | Likely Benign | 0.207 | Likely Benign | Likely Benign | -0.43 | Likely Benign | 0.1 | 0.60 | Ambiguous | 0.09 | Likely Benign | -0.66 | Ambiguous | 0.285 | Likely Benign | 1.22 | Neutral | 0.005 | Benign | 0.009 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 0.1218 | 0.1163 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1855A>G | T619A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T619A missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools cluster into two groups: benign predictions come from SIFT, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the change as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points toward a pathogenic effect, 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 | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -6.341 | Likely Benign | 0.672 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.61 | Ambiguous | 0.53 | Ambiguous | 0.613 | Likely Pathogenic | -4.21 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.27 | Pathogenic | 0.17 | Tolerated | 0.3915 | 0.3109 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1855A>T | T619S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result. Overall, the majority of evidence points to a pathogenic effect for T619S, and this conclusion does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | Uncertain | 1 | -8.608 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 1.09 | Ambiguous | 0.2 | 1.35 | Ambiguous | 1.22 | Ambiguous | 0.85 | Ambiguous | 0.602 | Likely Pathogenic | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0.3255 | 0.2860 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1856C>G | T619S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T619S missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized remains benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -8.608 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 1.09 | Ambiguous | 0.2 | 1.35 | Ambiguous | 1.22 | Ambiguous | 0.85 | Ambiguous | 0.523 | Likely Pathogenic | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0.3255 | 0.2860 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||
| c.1858T>A | S620T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized, and Rosetta. Those that predict pathogenicity are SGM‑Consensus, REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of tools lean toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -9.171 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 0.52 | Ambiguous | 0.1 | -0.40 | Likely Benign | 0.06 | Likely Benign | 0.30 | Likely Benign | 0.551 | Likely Pathogenic | -1.99 | Neutral | 0.896 | Possibly Damaging | 0.933 | Probably Damaging | -1.25 | Pathogenic | 0.14 | Tolerated | 0.1288 | 0.5199 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1858T>C | S620P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: 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. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -12.208 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 4.89 | Destabilizing | 0.5 | 12.23 | Destabilizing | 8.56 | Destabilizing | 0.73 | Ambiguous | 0.834 | Likely Pathogenic | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.35 | Pathogenic | 0.02 | Affected | 0.2147 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1858T>G | S620A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. 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, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from these analyses suggests a deleterious effect. Consequently, the variant is most likely benign based on the aggregate predictions, 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 Benign | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -4.637 | Likely Benign | 0.088 | Likely Benign | Likely Benign | -0.42 | Likely Benign | 0.0 | -0.90 | Ambiguous | -0.66 | Ambiguous | -0.19 | Likely Benign | 0.375 | Likely Benign | -0.52 | Neutral | 0.968 | Probably Damaging | 0.994 | Probably Damaging | -1.27 | Pathogenic | 0.66 | Tolerated | 0.4950 | 0.3636 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.185A>G | D62G 2D AIThe SynGAP1 D62G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 not available. 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -4.047 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.76 | Neutral | 0.012 | Benign | 0.032 | Benign | 4.07 | Benign | 0.00 | Affected | 0.4016 | 0.6081 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1862G>A | R621Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621Q is listed in ClinVar (ID 578137.0) as benign and is present in gnomAD (variant ID 6‑33440914‑G‑A). Functional prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the preponderance of predictions indicates a likely pathogenic effect, which contradicts the benign classification reported in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | 0.621 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2590 | 0.1963 | 1 | 1 | 1.0 | -28.06 | 243.7 | 54.3 | 0.0 | 0.0 | -0.4 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||||||
| c.1864A>G | T622A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622A 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 FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools with uncertain or inconclusive results—AlphaMissense‑Optimized, Rosetta, Foldetta, and premPS—are treated as unavailable for pathogenicity assessment. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for T622A, 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 | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -10.953 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.54 | Ambiguous | 0.75 | Ambiguous | 0.893 | Likely Pathogenic | -4.58 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.52 | Pathogenic | 0.01 | Affected | 0.3191 | 0.3091 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1864A>T | T622S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622S is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, whereas the SGM‑Consensus predicts it to be likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No other folding‑stability tools provide conclusive evidence. Overall, the preponderance of predictions, including the SGM‑Consensus, indicates that T622S 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 | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -9.840 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.07 | Ambiguous | 0.80 | Ambiguous | 0.705 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.09 | Tolerated | 0.2523 | 0.3183 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1865C>G | T622S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622S is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, whereas the SGM‑Consensus predicts it to be likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No other folding‑stability tools provide conclusive evidence. Overall, the preponderance of predictions, including the SGM‑Consensus, indicates that T622S 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 | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -9.840 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.07 | Ambiguous | 0.80 | Ambiguous | 0.595 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.09 | Tolerated | 0.2523 | 0.3183 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| 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.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.1876A>T | I626F 2D 3DClick to see structure in 3D Viewer AISynGAP1 I626F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Taken together, the overwhelming majority of evidence indicates that I626F is 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 | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -14.483 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 4.37 | Destabilizing | 0.3 | 2.12 | Destabilizing | 3.25 | Destabilizing | 0.66 | Ambiguous | 0.631 | Likely Pathogenic | -3.78 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0481 | 0.1964 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| 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.1879G>C | A627P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A627P is not reported in ClinVar and is absent from gnomAD. Prediction tools were grouped by consensus: Benign – none; Pathogenic – SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. High‑accuracy methods specifically: AlphaMissense‑Optimized predicts pathogenicity; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, 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 | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -15.404 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.78 | Destabilizing | 0.3 | 7.84 | Destabilizing | 6.81 | Destabilizing | 1.13 | Destabilizing | 0.740 | Likely Pathogenic | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.43 | Pathogenic | 0.01 | Affected | 0.1752 | 0.3422 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1879G>T | A627S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A627S 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, PROVEAN, and ESM1b. The remaining tools—FoldX, Foldetta, and premPS—return 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) is inconclusive due to a 2‑vs‑2 split, and Foldetta is uncertain. Overall, the majority of available predictions lean toward a benign impact. Thus, 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 | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -10.782 | Likely Pathogenic | 0.329 | Likely Benign | Likely Benign | 1.11 | Ambiguous | 0.2 | 2.05 | Destabilizing | 1.58 | Ambiguous | 0.71 | Ambiguous | 0.316 | Likely Benign | -2.94 | Deleterious | 0.411 | Benign | 0.387 | Benign | 2.78 | Benign | 0.11 | Tolerated | 0.2266 | 0.4224 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.187G>A | E63K 2D AIThe SynGAP1 E63K missense variant (ClinVar ID 2830630.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict a pathogenic outcome. AlphaMissense‑Optimized is inconclusive, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. Overall, the high‑accuracy consensus leans toward a benign effect, and this assessment does not contradict the ClinVar status of uncertainty. 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 | -4.976 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.70 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1995 | 0.7261 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.1880C>G | A627G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627G 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 comprise SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of evidence points to 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. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -11.716 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.38 | Ambiguous | 0.1 | 2.07 | Destabilizing | 1.73 | Ambiguous | 1.25 | Destabilizing | 0.458 | Likely Benign | -3.96 | Deleterious | 0.997 | Probably Damaging | 0.876 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1921 | 0.2990 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1882A>C | K628Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628Q 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, and Foldetta, all of which score the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The premPS tool yields an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | -12.263 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.0 | -0.16 | Likely Benign | 0.15 | Likely Benign | 0.95 | Ambiguous | 0.587 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.3444 | 0.1358 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1888A>T | I630F 2D 3DClick to see structure in 3D Viewer AISynGAP1 I630F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and premPS and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting likely pathogenic, and Foldetta yielding an uncertain stability change. Overall, the preponderance of evidence points to a pathogenic impact for I630F. This conclusion is not contradicted by ClinVar, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.036106 | Uncertain | 0.966 | 0.236 | 0.000 | -13.669 | Likely Pathogenic | 0.705 | Likely Pathogenic | Likely Benign | 2.52 | Destabilizing | 0.3 | 0.76 | Ambiguous | 1.64 | Ambiguous | 0.75 | Ambiguous | 0.782 | Likely Pathogenic | -3.12 | Deleterious | 0.935 | Possibly Damaging | 0.473 | Possibly Damaging | -1.46 | Pathogenic | 0.01 | Affected | 0.0443 | 0.1964 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| 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.1891C>A | Q631K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q631K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Uncertain or inconclusive results are reported by Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect; the SGM‑Consensus, a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; AlphaMissense‑Optimized remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not conflict with 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 | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -15.194 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.38 | Likely Benign | 0.88 | Ambiguous | 0.596 | Likely Pathogenic | -3.98 | Deleterious | 0.958 | Probably Damaging | 0.931 | Probably Damaging | 2.79 | Benign | 0.01 | Affected | 0.1288 | 0.2157 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1892A>G | Q631R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions come from FoldX, Foldetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact for Q631R, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -14.881 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | -0.34 | Likely Benign | 0.1 | 0.83 | Ambiguous | 0.25 | Likely Benign | 0.77 | Ambiguous | 0.627 | Likely Pathogenic | -3.98 | Deleterious | 0.973 | Probably Damaging | 0.969 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1193 | 0.0653 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1895A>G | N632S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632S 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—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 majority of available predictions (six benign vs. three pathogenic) support a benign classification, and this does not contradict the lack of ClinVar annotation. Thus, 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. | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -7.677 | In-Between | 0.291 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.80 | Ambiguous | 0.41 | Likely Benign | 0.469 | Likely Benign | -3.85 | Deleterious | 0.718 | Possibly Damaging | 0.086 | Benign | -1.37 | Pathogenic | 0.12 | Tolerated | 0.3302 | 0.6486 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.1897C>G | L633V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633V is not reported in ClinVar and is present in the gnomAD database (ID 6‑33440949‑C‑G). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus, and Foldetta; the Rosetta score is uncertain and therefore not considered. High‑accuracy methods give a pathogenic consensus: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic impact for L633V, 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. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | 6-33440949-C-G | 1 | 6.20e-7 | -9.992 | Likely Pathogenic | 0.760 | Likely Pathogenic | Likely Benign | 2.32 | Destabilizing | 0.2 | 1.71 | Ambiguous | 2.02 | Destabilizing | 1.32 | Destabilizing | 0.327 | Likely Benign | -2.99 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.86 | Benign | 0.03 | Affected | 3.37 | 34 | 0.1517 | 0.2766 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1900G>A | A634T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, while only FATHMM predicts benign. Two tools give uncertain results: AlphaMissense‑Optimized and Foldetta. High‑accuracy assessment shows that the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic classification, whereas AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for A634T, 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 | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -12.451 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.56 | Destabilizing | 0.1 | 1.11 | Ambiguous | 1.84 | Ambiguous | 1.34 | Destabilizing | 0.603 | Likely Pathogenic | -3.98 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1397 | 0.5240 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1900G>C | A634P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to 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—classify the variant as 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 pathogenic. No prediction or folding 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 none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -15.372 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.17 | Destabilizing | 0.2 | 7.72 | Destabilizing | 5.95 | Destabilizing | 1.39 | Destabilizing | 0.745 | Likely Pathogenic | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.2090 | 0.3429 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1900G>T | A634S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A634S 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 FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are inconclusive. 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 majority of evidence points to a pathogenic impact, 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. | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -9.706 | Likely Pathogenic | 0.434 | Ambiguous | Likely Benign | 0.91 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.10 | Ambiguous | 0.77 | Ambiguous | 0.506 | Likely Pathogenic | -2.99 | Deleterious | 0.953 | Possibly Damaging | 0.985 | Probably Damaging | 2.67 | Benign | 0.05 | Affected | 0.2607 | 0.4231 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1901C>G | A634G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A634G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls are made by Rosetta, premPS, PROVEAN, both polyPhen‑2 versions, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta give uncertain results. High‑accuracy assessments indicate AlphaMissense‑Optimized predicts benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic interpretation. Therefore, the variant is most likely pathogenic, 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 | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -10.685 | Likely Pathogenic | 0.613 | Likely Pathogenic | Likely Benign | 1.63 | Ambiguous | 0.1 | 2.27 | Destabilizing | 1.95 | Ambiguous | 1.09 | Destabilizing | 0.418 | Likely Benign | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | 2.69 | Benign | 0.15 | Tolerated | 0.2182 | 0.3187 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1904A>G | N635S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635S is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440956-A-G). Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions lean toward 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. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | Conflicting | 4 | 6-33440956-A-G | 10 | 6.20e-6 | -9.002 | Likely Pathogenic | 0.101 | Likely Benign | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.74 | Ambiguous | 0.95 | Ambiguous | 0.104 | Likely Benign | -4.45 | Deleterious | 0.261 | Benign | 0.044 | Benign | 3.06 | Benign | 0.05 | Affected | 3.37 | 34 | 0.2816 | 0.4279 | 1 | 1 | 2.7 | -27.03 | 196.0 | 30.9 | 0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | In the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations. | ||||||||||||||
| c.1905C>A | N635K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict pathogenicity: 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, also indicates a likely pathogenic outcome. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for N635K, 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 | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1905C>G | N635K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM Consensus as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the preponderance of evidence from multiple in silico predictors indicates that the variant is most likely pathogenic, 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 | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1906T>A | F636I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636I 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—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion 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 | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.031 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.96 | Destabilizing | 0.2 | 4.57 | Destabilizing | 3.77 | Destabilizing | 1.10 | Destabilizing | 0.501 | Likely Pathogenic | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.977 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1660 | 0.2153 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1909T>A | S637T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637T 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, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: 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) predicts benign. 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 | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -4.116 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.1 | -0.91 | Ambiguous | -0.28 | Likely Benign | -0.39 | Likely Benign | 0.067 | Likely Benign | -0.19 | Neutral | 0.086 | Benign | 0.019 | Benign | 3.45 | Benign | 0.19 | Tolerated | 0.1675 | 0.4572 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1909T>C | S637P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments give a pathogenic signal: the SGM Consensus predicts likely pathogenic, Foldetta predicts destabilizing pathogenic effects, whereas AlphaMissense‑Optimized remains uncertain. Overall, the balance of evidence favors a pathogenic 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. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -11.455 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 6.73 | Destabilizing | 0.1 | 6.36 | Destabilizing | 6.55 | Destabilizing | 0.44 | Likely Benign | 0.192 | Likely Benign | -3.12 | Deleterious | 0.946 | Possibly Damaging | 0.360 | Benign | 3.36 | Benign | 0.03 | Affected | 0.2374 | 0.4094 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1909T>G | S637A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 (HumDiv and HumVar), REVEL, FoldX, and premPS. No tool predicts a pathogenic outcome. 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, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive (Uncertain). Taken together, the overwhelming majority of evidence indicates a benign effect. The variant’s status 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 | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -4.186 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.65 | Ambiguous | 0.22 | Likely Benign | 0.078 | Likely Benign | -0.64 | Neutral | 0.120 | Benign | 0.182 | Benign | 3.41 | Benign | 1.00 | Tolerated | 0.4853 | 0.2996 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1912A>C | K638Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K638Q 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, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. 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. Overall, the majority of evidence points to a benign impact, 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. | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.561 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 0.45 | Likely Benign | 0.0 | 0.37 | Likely Benign | 0.41 | Likely Benign | 0.22 | Likely Benign | 0.421 | Likely Benign | -3.60 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.12 | Tolerated | 0.3623 | 0.0920 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.1914G>C | K638N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638N is not reported in ClinVar and is absent from gnomAD. 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. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of 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 currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.420 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.1 | 0.90 | Ambiguous | 0.82 | Ambiguous | 0.40 | Likely Benign | 0.256 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.2875 | 0.1126 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1914G>T | K638N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638N is not reported in ClinVar and is absent from gnomAD. 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. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of 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 currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.420 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.1 | 0.90 | Ambiguous | 0.82 | Ambiguous | 0.40 | Likely Benign | 0.256 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.2875 | 0.1126 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1915T>A | F639I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, 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 | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.548 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.3 | 0.47 | Likely Benign | 2.40 | Destabilizing | 1.44 | Destabilizing | 0.545 | Likely Pathogenic | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.659 | Possibly Damaging | 3.08 | Benign | 0.01 | Affected | 0.2070 | 0.1755 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1918A>G | T640A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN, REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT all score the substitution as benign. No tool predicts pathogenicity; only Rosetta yields an uncertain result. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Taken together, the evidence overwhelmingly supports a benign classification for T640A, and this conclusion does not contradict any ClinVar annotation (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -3.068 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.14 | Likely Benign | 0.1 | 0.93 | Ambiguous | 0.54 | Ambiguous | -0.17 | Likely Benign | 0.078 | Likely Benign | 0.51 | Neutral | 0.009 | Benign | 0.001 | Benign | 3.51 | Benign | 0.42 | Tolerated | 0.3834 | 0.3202 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1918A>T | T640S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640S is listed in ClinVar as Benign (ClinVar ID 2980241.0) and is present in the gnomAD database (gnomAD ID 6‑33441177‑A‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX, which is treated as unavailable. High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Overall, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | Benign | 1 | 6-33441177-A-T | 1 | 6.20e-7 | -2.371 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.78 | Ambiguous | 0.1 | 0.43 | Likely Benign | -0.18 | Likely Benign | -0.30 | Likely Benign | 0.088 | Likely Benign | 0.92 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.60 | Benign | 0.33 | Tolerated | 3.37 | 30 | 0.3406 | 0.3484 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||
| c.1919C>G | T640S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, premPS, Foldetta, Rosetta, REVEL, and the SGM‑Consensus score (Likely Benign) all classify the change as tolerated. No tool predicts pathogenicity; the only inconclusive result is from FoldX, which is listed as Uncertain. High‑accuracy methods corroborate the benign assessment: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. Consequently, the variant is most likely benign, and this conclusion does not contradict 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 Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -2.371 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.78 | Ambiguous | 0.1 | 0.43 | Likely Benign | -0.18 | Likely Benign | -0.30 | Likely Benign | 0.109 | Likely Benign | 0.92 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.60 | Benign | 0.33 | Tolerated | 3.37 | 30 | 0.3406 | 0.3484 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||
| c.1921T>A | S641T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. Rosetta also predicts a benign outcome, while FoldX and Foldetta are inconclusive (marked “Uncertain”). No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, 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 Benign | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.637 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.3 | 0.41 | Likely Benign | 0.62 | Ambiguous | 0.13 | Likely Benign | 0.043 | Likely Benign | -1.50 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.39 | Benign | 0.09 | Tolerated | 0.1505 | 0.5888 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1921T>C | S641P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and SIFT. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, 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. | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.907 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.3 | 0.07 | Likely Benign | 0.90 | Ambiguous | 0.59 | Ambiguous | 0.205 | Likely Benign | -3.05 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.34 | Benign | 0.04 | Affected | 0.2289 | 0.5791 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.1921T>G | S641A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641A is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, 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 Benign | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.103 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.2 | -0.28 | Likely Benign | 0.05 | Likely Benign | 0.27 | Likely Benign | 0.067 | Likely Benign | -2.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.43 | Benign | 0.17 | Tolerated | 0.4873 | 0.4680 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1924A>C | K642Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K642Q is not reported in ClinVar and has no allele in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. No other high‑confidence predictions are available. Overall, the balance of evidence leans toward a benign effect, with the single high‑accuracy pathogenic signal from SGM‑Consensus not contradicting the lack of ClinVar annotation. Thus, the variant is most likely benign, and this assessment does not conflict with ClinVar status. 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 | -12.186 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.13 | Likely Benign | 0.42 | Likely Benign | 0.380 | Likely Benign | -3.88 | Deleterious | 0.576 | Possibly Damaging | 0.383 | Benign | 2.87 | Benign | 0.02 | Affected | 0.4477 | 0.1253 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1926G>C | K642N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K642N 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 REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. With two of the three high‑accuracy tools supporting pathogenicity and an overall balance 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. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.423 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.273 | Likely Benign | -4.88 | Deleterious | 0.958 | Probably Damaging | 0.392 | Benign | 2.88 | Benign | 0.00 | Affected | 0.3553 | 0.1590 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1926G>T | K642N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642N 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, FoldX, Rosetta, Foldetta, premPS, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar (benign). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, seven tools favor pathogenicity versus six favoring benign, and the high‑accuracy predictions are mixed. Thus, the variant is most likely pathogenic based on the preponderance of evidence, 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.423 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.274 | Likely Benign | -4.88 | Deleterious | 0.958 | Probably Damaging | 0.392 | Benign | 2.88 | Benign | 0.00 | Affected | 0.3553 | 0.1590 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.192A>G | I64M 2D AIThe SynGAP1 missense variant I64M is listed in gnomAD (ID 6‑33425800‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, 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 SIFT, while AlphaMissense‑Default remains uncertain. 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, 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 | 0.422041 | Structured | 0.475481 | Uncertain | 0.478 | 0.747 | 0.125 | 6-33425800-A-G | 2 | 1.24e-6 | -4.327 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.047 | Likely Benign | -0.05 | Neutral | 0.637 | Possibly Damaging | 0.047 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0568 | 0.2310 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||
| c.1930G>C | D644H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D644H 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, Foldetta, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. No other high‑accuracy predictions are available. Overall, the majority of evidence points to 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -6.786 | Likely Benign | 0.771 | Likely Pathogenic | Likely Benign | 0.34 | Likely Benign | 0.1 | -0.83 | Ambiguous | -0.25 | Likely Benign | 0.09 | Likely Benign | 0.284 | Likely Benign | -2.93 | Deleterious | 0.789 | Possibly Damaging | 0.158 | Benign | 3.43 | Benign | 0.07 | Tolerated | 0.1656 | 0.6306 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||
| c.1931A>G | D644G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D644G 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and AlphaMissense‑Default (polyPhen‑2 HumVar is benign). 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‑to‑2 split. Overall, the majority of evidence points to 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. | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -4.496 | Likely Benign | 0.602 | Likely Pathogenic | Likely Benign | 0.13 | Likely Benign | 0.0 | -0.18 | Likely Benign | -0.03 | Likely Benign | 0.04 | Likely Benign | 0.271 | Likely Benign | -4.38 | Deleterious | 0.456 | Possibly Damaging | 0.069 | Benign | 3.46 | Benign | 0.14 | Tolerated | 0.4035 | 0.5610 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.1933T>A | F645I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F645I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are given by premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) report uncertain or inconclusive outcomes. High‑accuracy assessments indicate that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is uncertain. Overall, the majority of evaluated predictors (five pathogenic vs four benign) lean toward a pathogenic effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for F645I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -13.055 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 1.12 | Ambiguous | 0.2 | 1.68 | Ambiguous | 1.40 | Ambiguous | 1.01 | Destabilizing | 0.299 | Likely Benign | -4.24 | Deleterious | 0.190 | Benign | 0.019 | Benign | 3.44 | Benign | 0.04 | Affected | 0.1920 | 0.2891 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1939G>A | G647S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from Rosetta and premPS, which are treated as unavailable. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the evidence strongly favors a benign classification, and this is consistent with its absence from ClinVar. The variant is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | -2.175 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.05 | Likely Benign | 0.1 | -0.75 | Ambiguous | -0.35 | Likely Benign | -0.56 | Ambiguous | 0.037 | Likely Benign | 0.65 | Neutral | 0.002 | Benign | 0.004 | Benign | 3.48 | Benign | 0.89 | Tolerated | 0.2409 | 0.3959 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.193C>G | H65D 2D AIThe SynGAP1 H65D missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is classified as Uncertain. 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 | 0.411940 | Structured | 0.476188 | Uncertain | 0.458 | 0.758 | 0.125 | -2.240 | Likely Benign | 0.937 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.78 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.17 | Benign | 0.00 | Affected | 0.2142 | 0.1828 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.1940G>C | G647A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are Rosetta, Foldetta, 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 Uncertain. Taken together, the overwhelming majority of evidence indicates a benign effect for G647A, 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 | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | -0.266 | Likely Benign | 0.078 | Likely Benign | Likely Benign | -0.18 | Likely Benign | 0.0 | -0.99 | Ambiguous | -0.59 | Ambiguous | -0.69 | Ambiguous | 0.037 | Likely Benign | 0.48 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.55 | Benign | 0.81 | Tolerated | 0.3558 | 0.4136 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1942T>A | F648I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F648I resides in the GAP domain. ClinVar contains no entry for this change, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also yields a pathogenic prediction. Taken together, the evidence overwhelmingly supports a pathogenic classification for F648I, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -11.912 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.49 | Destabilizing | 0.1 | 2.49 | Destabilizing | 2.49 | Destabilizing | 1.05 | Destabilizing | 0.472 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 0.1673 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1949A>G | N650S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650S 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 REVEL and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results come from AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, and premPS. For high‑accuracy methods, AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the majority of available predictions support a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. 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 | -11.291 | Likely Pathogenic | 0.916 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.11 | Ambiguous | 0.77 | Ambiguous | 0.395 | Likely Benign | -4.98 | Deleterious | 0.996 | Probably Damaging | 0.606 | Possibly Damaging | 3.06 | Benign | 0.02 | Affected | 0.3791 | 0.5090 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| 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.196C>G | P66A 2D AIThe SynGAP1 P66A missense variant (ClinVar ID 1303518.0) is listed as “Uncertain” and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. Separately, the high‑accuracy AlphaMissense‑Optimized result is “Uncertain,” the SGM‑Consensus remains “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the predictions are mixed, but the majority of high‑confidence tools lean toward a benign effect. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict the ClinVar status of uncertainty. 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 | Uncertain | 1 | -2.845 | Likely Benign | 0.891 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.56 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3467 | 0.5138 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.196C>T | P66S 2D AIThe SynGAP1 missense variant P66S is listed in ClinVar (ID 1915017.0) as benign and is present in gnomAD (variant ID 6‑33425804‑C‑T). 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). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, which is consistent with the ClinVar designation and does not contradict the reported status. 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 | Benign | 1 | 6-33425804-C-T | 2 | 1.24e-6 | -2.760 | Likely Benign | 0.929 | Likely Pathogenic | Ambiguous | 0.081 | Likely Benign | -1.69 | Neutral | 0.909 | Possibly Damaging | 0.641 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3417 | 0.5463 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.1973G>A | G658D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G658D is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33441232‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome, while Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta, which integrates FoldX‑MD and Rosetta, is also inconclusive. Overall, the preponderance of evidence points to a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | Uncertain | 1 | 6-33441232-G-A | 3 | 1.86e-6 | -7.786 | In-Between | 0.442 | Ambiguous | Likely Benign | -0.40 | Likely Benign | 0.1 | -0.59 | Ambiguous | -0.50 | Ambiguous | 0.46 | Likely Benign | 0.144 | Likely Benign | -2.64 | Deleterious | 0.008 | Benign | 0.005 | Benign | 3.53 | Benign | 0.38 | Tolerated | 3.39 | 24 | 0.2106 | 0.2333 | 1 | -1 | -3.1 | 58.04 | 219.8 | -84.3 | 0.0 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Gly658, located on the outer surface of an α helix (res. Ser641-Glu666), weakens the helix integrity at that spot, which is necessary for the kink in the middle of the long helix. In the variant simulations, the carboxylic acid side chain of Asp658 is on the surface of the α helix and is not involved in any interactions. However, aspartate is not as effective a breaker of the secondary structure element as glycine, which may lead to misfolding. | ||||||||||||||
| c.1973G>C | G658A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, and the SGM‑Consensus score indicates a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized returns a benign prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign result, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain outcome. Taken together, the evidence overwhelmingly supports a benign impact for G658A, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -4.303 | Likely Benign | 0.083 | Likely Benign | Likely Benign | -0.34 | Likely Benign | 0.0 | -0.75 | Ambiguous | -0.55 | Ambiguous | -0.18 | Likely Benign | 0.072 | Likely Benign | -0.93 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.47 | Benign | 0.36 | Tolerated | 0.3937 | 0.3352 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1975T>A | S659T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. Only Rosetta reports an uncertain outcome, which is treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -5.693 | Likely Benign | 0.157 | Likely Benign | Likely Benign | -0.15 | Likely Benign | 0.0 | -0.74 | Ambiguous | -0.45 | Likely Benign | 0.42 | Likely Benign | 0.106 | Likely Benign | -2.04 | Neutral | 0.069 | Benign | 0.011 | Benign | 3.41 | Benign | 0.39 | Tolerated | 0.1505 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1975T>C | S659P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are SGM‑Consensus, Rosetta, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, premPS, and Foldetta—are treated as unavailable. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized reports a benign change, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta’s stability assessment is uncertain. Overall, the balance of evidence leans toward a pathogenic effect, but the presence of a strong benign prediction from AlphaMissense‑Optimized and the lack of ClinVar annotation means the variant’s clinical significance remains uncertain and does not contradict existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -10.461 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | -0.73 | Ambiguous | 0.3 | 2.98 | Destabilizing | 1.13 | Ambiguous | 0.73 | Ambiguous | 0.224 | Likely Benign | -3.26 | Deleterious | 0.932 | Possibly Damaging | 0.245 | Benign | 3.39 | Benign | 0.18 | Tolerated | 0.2207 | 0.5553 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1975T>G | S659A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while ESM1b remains uncertain. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -7.066 | In-Between | 0.117 | Likely Benign | Likely Benign | -0.31 | Likely Benign | 0.0 | 0.02 | Likely Benign | -0.15 | Likely Benign | 0.14 | Likely Benign | 0.088 | Likely Benign | -2.22 | Neutral | 0.097 | Benign | 0.114 | Benign | 3.50 | Benign | 0.64 | Tolerated | 0.4842 | 0.3813 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1981C>A | Q661K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661K 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, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Only ESM1b predicts a pathogenic outcome, while 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 (2 benign vs. 1 pathogenic, with one uncertain), and Foldetta also predicts benign stability. Overall, the preponderance of evidence indicates that the variant 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. | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -10.581 | Likely Pathogenic | 0.400 | Ambiguous | Likely Benign | -0.01 | Likely Benign | 0.0 | -0.18 | Likely Benign | -0.10 | Likely Benign | 0.04 | Likely Benign | 0.108 | Likely Benign | -1.89 | Neutral | 0.098 | Benign | 0.030 | Benign | 3.59 | Benign | 0.42 | Tolerated | 0.1756 | 0.3592 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||
| c.1982A>G | Q661R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661R 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‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are polyPhen2_HumDiv and ESM1b. FoldX, Rosetta, Foldetta, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the majority of available evidence points to 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. | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -10.386 | Likely Pathogenic | 0.479 | Ambiguous | Likely Benign | -1.12 | Ambiguous | 0.0 | -0.59 | Ambiguous | -0.86 | Ambiguous | -0.15 | Likely Benign | 0.281 | Likely Benign | -2.06 | Neutral | 0.812 | Possibly Damaging | 0.251 | Benign | 3.52 | Benign | 0.18 | Tolerated | 0.1502 | 0.2196 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||
| c.1984C>A | Q662K 2D AIThe SynGAP1 missense variant Q662K 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, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while only ESM1b predicts pathogenicity. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a Likely Benign verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign effect. No conflicting evidence is present. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -8.892 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | -0.02 | Likely Benign | 0.2 | 0.03 | Likely Benign | 0.01 | Likely Benign | -0.04 | Likely Benign | 0.108 | Likely Benign | -0.80 | Neutral | 0.321 | Benign | 0.030 | Benign | 3.49 | Benign | 0.37 | Tolerated | 0.2391 | 0.3198 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1985A>G | Q662R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, FATHMM, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, FoldX, and Rosetta all predict benign. No tool in the dataset indicates pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Thus, based on the available predictions, 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 | GAP | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -6.678 | Likely Benign | 0.300 | Likely Benign | Likely Benign | -0.41 | Likely Benign | 0.0 | 0.10 | Likely Benign | -0.16 | Likely Benign | -0.42 | Likely Benign | 0.159 | Likely Benign | 0.49 | Neutral | 0.428 | Benign | 0.095 | Benign | 3.48 | Benign | 1.00 | Tolerated | 0.2023 | 0.1391 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1987T>A | F663I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663I 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—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates 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 agreement among these tools, 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 | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -15.006 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.63 | Destabilizing | 0.1 | 4.51 | Destabilizing | 3.57 | Destabilizing | 1.60 | Destabilizing | 0.641 | Likely Pathogenic | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 0.1740 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| 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.19T>A | S7T 2D AIThe SynGAP1 missense variant S7T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -4.182 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.26 | Neutral | 0.024 | Benign | 0.007 | Benign | 4.13 | Benign | 0.00 | Affected | 0.1688 | 0.5919 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.19T>G | S7A 2D AIThe SynGAP1 missense variant S7A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all of which are benign, so the consensus is benign. AlphaMissense‑Optimized 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 available predictions, 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 | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -3.613 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.10 | Neutral | 0.002 | Benign | 0.001 | Benign | 4.18 | Benign | 0.00 | Affected | 0.5485 | 0.4355 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2002T>A | S668T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668T 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 REVEL, premPS, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of predictions leans toward pathogenicity, 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 | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -11.860 | Likely Pathogenic | 0.703 | Likely Pathogenic | Likely Benign | 1.73 | Ambiguous | 0.7 | 0.89 | Ambiguous | 1.31 | Ambiguous | 0.27 | Likely Benign | 0.238 | Likely Benign | -2.99 | Deleterious | 0.844 | Possibly Damaging | 0.198 | Benign | 3.24 | Benign | 0.02 | Affected | 0.1212 | 0.5918 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| 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.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.2006A>G | N669S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33441265‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta (combining FoldX‑MD and Rosetta) is also inconclusive. No folding‑stability metrics (FoldX, Rosetta, Foldetta) provide definitive evidence. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the absence 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. | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | 6-33441265-A-G | 3 | 1.86e-6 | -8.369 | Likely Pathogenic | 0.187 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.22 | Ambiguous | 0.35 | Likely Benign | 0.210 | Likely Benign | -4.02 | Deleterious | 0.999 | Probably Damaging | 0.960 | Probably Damaging | 3.52 | Benign | 0.14 | Tolerated | 3.39 | 27 | 0.3521 | 0.4480 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.2007T>A | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the majority of evidence points toward a pathogenic 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 Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2007T>G | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by 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 pathogenicity, SGM‑Consensus concurs, and the Foldetta stability analysis is inconclusive and therefore not used as evidence. No other tools provide definitive support for benignity. Consequently, the preponderance of evidence points to a pathogenic impact. 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. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2011G>A | D671N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D671N is reported in gnomAD (6‑33441270‑G‑A) but has no ClinVar entry. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. 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, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus remains pathogenic. Overall, the predictions are split, with a slight bias toward benign outcomes from the majority of tools, but the consensus pathogenic signal from SGM and several high‑confidence predictors suggests uncertainty. The variant is most likely benign based on the preponderance of benign predictions, and this 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 | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | 6-33441270-G-A | -10.347 | Likely Pathogenic | 0.685 | Likely Pathogenic | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.29 | Likely Benign | 0.19 | Likely Benign | 0.184 | Likely Benign | -3.19 | Deleterious | 0.887 | Possibly Damaging | 0.592 | Possibly Damaging | 3.36 | Benign | 0.02 | Affected | 3.39 | 27 | 0.1298 | 0.6463 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.2011G>C | D671H 2D 3DClick to see structure in 3D Viewer AISynGAP1 D671H is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the balance of evidence leans toward pathogenicity, and this 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. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.501 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.0 | 0.29 | Likely Benign | 0.39 | Likely Benign | 0.09 | Likely Benign | 0.300 | Likely Benign | -4.35 | Deleterious | 0.999 | Probably Damaging | 0.939 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.1627 | 0.6509 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.2012A>G | D671G 2D AIThe SynGAP1 D671G 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 predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No evidence from these tools contradicts the pathogenic prediction. Overall, the balance of evidence favors a pathogenic classification for D671G, and this conclusion is consistent with the absence of a ClinVar entry. 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 | -10.346 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.50 | Ambiguous | 0.5 | 1.53 | Ambiguous | 1.02 | Ambiguous | 0.00 | Likely Benign | 0.279 | Likely Benign | -4.78 | Deleterious | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.4032 | 0.5823 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2014A>G | T672A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672A is listed in ClinVar as Benign (ClinVar ID 2154412.0) and is present in gnomAD (variant ID 6‑33441273‑A‑G). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | Benign | 1 | 6-33441273-A-G | 3 | 1.86e-6 | -6.524 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.51 | Ambiguous | 0.3 | 1.15 | Ambiguous | 0.83 | Ambiguous | 0.65 | Ambiguous | 0.046 | Likely Benign | -3.20 | Deleterious | 0.006 | Benign | 0.002 | Benign | 3.44 | Benign | 0.12 | Tolerated | 3.40 | 25 | 0.3687 | 0.4380 | 1 | 0 | 2.5 | -30.03 | 188.5 | 42.5 | -0.1 | 0.3 | 0.2 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. In the variant simulations, Ala672 can only form a hydrogen bond with Lys566 via its backbone carbonyl group. Consequently, it cannot maintain the Lys566-Glu666 salt bridge through hydrogen bonding, leading to a significant disruption of the intricate and stable hydrogen-bond network between the loop and the helices. | |||||||||||||
| c.2014A>T | T672S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign or likely benign. No tool predicts pathogenicity. High‑accuracy methods corroborate this: AlphaMissense‑Optimized reports benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Consequently, 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 | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | -4.932 | Likely Benign | 0.097 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.1 | 0.29 | Likely Benign | 0.08 | Likely Benign | 0.61 | Ambiguous | 0.044 | Likely Benign | -2.32 | Neutral | 0.006 | Benign | 0.010 | Benign | 3.43 | Benign | 0.09 | Tolerated | 0.3005 | 0.4282 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2020A>G | T674A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly favor a benign effect: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, REVEL, FoldX, premPS, Foldetta, and the SGM‑Consensus score all indicate benign or likely benign. No tool predicts pathogenicity; the only inconclusive result comes from Rosetta, which is listed as uncertain. High‑accuracy methods corroborate the benign assessment: 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 outputs) is benign. Based on the aggregate predictions, 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. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.915 | Likely Benign | 0.099 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.0 | 0.89 | Ambiguous | 0.38 | Likely Benign | 0.29 | Likely Benign | 0.052 | Likely Benign | -1.48 | Neutral | 0.398 | Benign | 0.045 | Benign | 3.45 | Benign | 0.28 | Tolerated | 0.4042 | 0.4845 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.2020A>T | T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available 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 | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.320 | Likely Benign | 0.082 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.11 | Likely Benign | -0.14 | Likely Benign | 0.084 | Likely Benign | 0.47 | Neutral | 0.107 | Benign | 0.033 | Benign | 3.47 | Benign | 1.00 | Tolerated | 0.3329 | 0.4938 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2021C>G | T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available 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 | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.320 | Likely Benign | 0.082 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.11 | Likely Benign | -0.14 | Likely Benign | 0.088 | Likely Benign | 0.47 | Neutral | 0.107 | Benign | 0.033 | Benign | 3.47 | Benign | 1.00 | Tolerated | 0.3329 | 0.4938 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2024A>G | N675S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675S 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, FATHMM, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools (premPS and ESM1b) return uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Taken together, the preponderance of evidence indicates that the variant is most likely benign, 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. | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -7.871 | In-Between | 0.081 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.0 | -0.43 | Likely Benign | -0.03 | Likely Benign | 0.61 | Ambiguous | 0.157 | Likely Benign | -3.78 | Deleterious | 0.993 | Probably Damaging | 0.606 | Possibly Damaging | 3.50 | Benign | 0.11 | Tolerated | 0.3462 | 0.7587 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| 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.2026A>G | S676G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676G 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, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. Two tools (ESM1b and premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta predicts a benign stability change. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -7.249 | In-Between | 0.117 | Likely Benign | Likely Benign | 0.38 | Likely Benign | 0.1 | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.67 | Ambiguous | 0.132 | Likely Benign | -2.74 | Deleterious | 0.855 | Possibly Damaging | 0.100 | Benign | 3.39 | Benign | 0.02 | Affected | 0.2772 | 0.4342 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.2027G>A | S676N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote). Only SIFT predicts a pathogenic outcome. Predictions that are inconclusive (FoldX, premPS, ESM1b) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is unavailable because one component (FoldX) is uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -7.486 | In-Between | 0.282 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.3 | -0.21 | Likely Benign | 0.20 | Likely Benign | 0.55 | Ambiguous | 0.099 | Likely Benign | -1.63 | Neutral | 0.438 | Benign | 0.036 | Benign | 3.42 | Benign | 0.05 | Affected | 0.1454 | 0.4599 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.2027G>C | S676T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (Uncertain) and Foldetta (Uncertain). 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 remains Uncertain. Overall, the consensus of available predictions indicates that the variant is most likely benign, 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 Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -5.621 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 0.34 | Likely Benign | 0.57 | Ambiguous | -0.36 | Likely Benign | 0.098 | Likely Benign | 0.91 | Neutral | 0.050 | Benign | 0.017 | Benign | 3.52 | Benign | 1.00 | Tolerated | 0.1575 | 0.6286 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2029A>G | S677G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and premPS—are treated as unavailable. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the evidence supports a benign classification for S677G, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -5.126 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.98 | Ambiguous | 0.1 | 1.20 | Ambiguous | 1.09 | Ambiguous | 0.64 | Ambiguous | 0.126 | Likely Benign | -1.38 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.30 | Benign | 0.26 | Tolerated | 0.2885 | 0.5325 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.2030G>A | S677N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677N is catalogued in gnomAD (6‑33441289‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while premPS and ESM1b are uncertain. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Thus, all available evidence supports a benign classification, and there is no conflict with ClinVar status (which is absent). The variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | 6-33441289-G-A | 1 | 6.20e-7 | -7.955 | In-Between | 0.111 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.5 | -0.15 | Likely Benign | 0.01 | Likely Benign | 0.89 | Ambiguous | 0.079 | Likely Benign | -2.05 | Neutral | 0.038 | Benign | 0.007 | Benign | 3.28 | Benign | 0.15 | Tolerated | 3.41 | 23 | 0.1763 | 0.5688 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||
| c.2030G>C | S677T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM all classify it as benign. No tool predicts pathogenicity. The only inconclusive results come from Rosetta (Uncertain) and Foldetta (Uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that S677T 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 | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -4.760 | Likely Benign | 0.063 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.3 | -0.85 | Ambiguous | -0.51 | Ambiguous | 0.15 | Likely Benign | 0.070 | Likely Benign | -0.97 | Neutral | 0.008 | Benign | 0.007 | Benign | 3.32 | Benign | 0.30 | Tolerated | 0.1775 | 0.6985 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2032A>G | S678G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678G 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‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, REVEL, FoldX, premPS, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is listed as “Uncertain.” High‑accuracy assessments further support a benign classification: 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 outputs) is benign. 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 | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -4.379 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.40 | Likely Benign | -0.24 | Likely Benign | 0.082 | Likely Benign | 1.90 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.43 | Benign | 1.00 | Tolerated | 0.2807 | 0.4961 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.2033G>A | S678N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678N is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33441292‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. High‑accuracy assessments are consistent: 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. Overall, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | 6-33441292-G-A | 1 | 6.20e-7 | -3.355 | Likely Benign | 0.139 | Likely Benign | Likely Benign | -0.10 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.29 | Likely Benign | 0.38 | Likely Benign | 0.067 | Likely Benign | -0.63 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.43 | Benign | 0.14 | Tolerated | 3.43 | 19 | 0.1435 | 0.4863 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||
| c.2033G>C | S678T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, 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). No tool predicts pathogenicity. High‑accuracy assessments likewise support a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Based on the unanimous computational evidence, the variant is most likely benign, 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 | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -5.389 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.41 | Likely Benign | 0.37 | Likely Benign | 0.14 | Likely Benign | 0.053 | Likely Benign | -1.82 | Neutral | 0.255 | Benign | 0.053 | Benign | 3.41 | Benign | 0.11 | Tolerated | 0.1494 | 0.6351 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2035T>A | F679I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM. In contrast, a majority of predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as Likely Pathogenic. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains pathogenic. Because the uncertain results are treated as unavailable, the clear majority of predictions support pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for F679I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -12.620 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.62 | Ambiguous | 0.4 | -0.27 | Likely Benign | 0.68 | Ambiguous | 0.88 | Ambiguous | 0.498 | Likely Benign | -5.91 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 3.59 | Benign | 0.01 | Affected | 0.1725 | 0.2322 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| 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.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.2042G>C | G681A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G681A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Predictions labeled uncertain include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; 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, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for G681A. 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -11.958 | Likely Pathogenic | 0.836 | Likely Pathogenic | Ambiguous | 1.77 | Ambiguous | 1.0 | 0.89 | Ambiguous | 1.33 | Ambiguous | 0.68 | Ambiguous | 0.354 | Likely Benign | -5.99 | Deleterious | 0.968 | Probably Damaging | 0.427 | Benign | 3.41 | Benign | 0.07 | Tolerated | 0.3879 | 0.4401 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2047A>T | I683F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683F 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 of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, while AlphaMissense‑Optimized and Foldetta are inconclusive and thus treated as unavailable evidence. Overall, the balance of evidence favors a pathogenic classification for I683F, 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. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.781 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.58 | Ambiguous | 0.59 | Ambiguous | 0.481 | Likely Benign | -3.99 | Deleterious | 0.971 | Probably Damaging | 0.499 | Possibly Damaging | 3.27 | Benign | 0.01 | Affected | 0.0770 | 0.2307 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2051A>G | D684G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome. Benign predictions come from premPS and FATHMM, whereas the remaining 12 tools—including REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive or missing. 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 | -14.238 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.0 | 4.07 | Destabilizing | 3.71 | Destabilizing | -0.30 | Likely Benign | 0.561 | Likely Pathogenic | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.3686 | 0.5403 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2056G>A | G686S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G686S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is also “Likely Pathogenic.” Uncertain predictions from Rosetta and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (a combined FoldX‑MD and Rosetta stability method) as benign. Overall, the majority of evidence points to a pathogenic effect, 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 | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -10.884 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.3 | 0.50 | Ambiguous | 0.40 | Likely Benign | 0.69 | Ambiguous | 0.537 | Likely Pathogenic | -5.29 | Deleterious | 0.998 | Probably Damaging | 0.929 | Probably Damaging | 3.46 | Benign | 0.06 | Tolerated | 0.2558 | 0.4355 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2057G>A | G686D 2D AIThe SynGAP1 missense variant G686D 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. Based on the collective evidence, 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. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -14.109 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 1.7 | 2.61 | Destabilizing | 2.31 | Destabilizing | 1.05 | Destabilizing | 0.563 | Likely Pathogenic | -6.28 | Deleterious | 1.000 | Probably Damaging | 0.967 | Probably Damaging | 3.40 | Benign | 0.00 | Affected | 0.1720 | 0.2196 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| 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.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.2068T>A | S690T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and polyPhen‑2 HumVar, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence leans 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 | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -11.380 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.39 | Likely Benign | 0.67 | Ambiguous | 0.311 | Likely Benign | -2.84 | Deleterious | 0.943 | Possibly Damaging | 0.267 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1059 | 0.4674 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| 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.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.2071A>G | T691A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while premPS and ESM1b are uncertain. The SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction contradicts the ClinVar status, which is currently unreported. Based on the preponderance of evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -7.840 | In-Between | 0.086 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.06 | Likely Benign | 0.69 | Ambiguous | 0.063 | Likely Benign | -1.84 | Neutral | 0.751 | Possibly Damaging | 0.131 | Benign | 3.49 | Benign | 0.33 | Tolerated | 0.2819 | 0.3251 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.2071A>T | T691S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, 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 ESM1b; premPS is uncertain. 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. Based on the overall consensus of the available predictions, 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 | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -9.274 | Likely Pathogenic | 0.123 | Likely Benign | Likely Benign | 0.44 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.34 | Likely Benign | 0.88 | Ambiguous | 0.041 | Likely Benign | -1.67 | Neutral | 0.860 | Possibly Damaging | 0.584 | Possibly Damaging | 3.49 | Benign | 0.61 | Tolerated | 0.2213 | 0.3343 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2077C>G | H693D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693D 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 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 | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -15.500 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.60 | Destabilizing | 0.1 | 2.03 | Destabilizing | 2.32 | Destabilizing | 1.62 | Destabilizing | 0.578 | Likely Pathogenic | -8.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.2166 | 0.1108 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.2080G>A | A694T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694T 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, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while FoldX 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 (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the overwhelming majority of evidence indicates a benign effect for A694T, 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 | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -3.565 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.1 | 0.11 | Likely Benign | 0.33 | Likely Benign | -0.26 | Likely Benign | 0.095 | Likely Benign | -0.71 | Neutral | 0.787 | Possibly Damaging | 0.098 | Benign | 3.46 | Benign | 0.17 | Tolerated | 0.1618 | 0.5440 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2080G>C | A694P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, while the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as Likely Pathogenic, with three of four votes pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for A694P. This conclusion is consistent with the absence of ClinVar annotation and gnomAD data, and there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -10.569 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.39 | Destabilizing | 0.2 | 5.59 | Destabilizing | 4.49 | Destabilizing | 0.82 | Ambiguous | 0.209 | Likely Benign | -2.77 | Deleterious | 0.988 | Probably Damaging | 0.578 | Possibly Damaging | 3.44 | Benign | 0.03 | Affected | 0.2265 | 0.3829 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2080G>T | A694S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The only inconclusive results come from Rosetta and premPS, which are listed as uncertain and do not influence the overall assessment. High‑accuracy predictors reinforce this view: 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 reports benign. Consequently, the variant is most likely benign, and this prediction 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 | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -0.326 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.41 | Likely Benign | -0.53 | Ambiguous | 0.092 | Likely Benign | 0.70 | Neutral | 0.013 | Benign | 0.021 | Benign | 3.57 | Benign | 1.00 | Tolerated | 0.2725 | 0.4231 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2081C>G | A694G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to 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 | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -3.420 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.0 | 1.16 | Ambiguous | 1.01 | Ambiguous | 0.86 | Ambiguous | 0.093 | Likely Benign | -1.90 | Neutral | 0.866 | Possibly Damaging | 0.171 | Benign | 3.50 | Benign | 0.05 | Affected | 0.2015 | 0.3387 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.2086C>G | L696V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L696V variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) report a pathogenic outcome; Rosetta remains inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for the variant, which 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 | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | Uncertain | 1 | -11.909 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 2.35 | Destabilizing | 0.1 | 1.85 | Ambiguous | 2.10 | Destabilizing | 1.46 | Destabilizing | 0.351 | Likely Benign | -2.79 | Deleterious | 0.992 | Probably Damaging | 0.970 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 3.46 | 13 | 0.1307 | 0.2830 | 1 | 2 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.209G>A | R70Q 2D AIThe SynGAP1 missense variant R70Q is reported in gnomAD (variant ID 6-33425817‑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 conclusion. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact. This assessment is not in conflict with ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.458981 | Uncertain | 0.392 | 0.793 | 0.375 | 6-33425817-G-A | 1 | 6.20e-7 | -3.399 | Likely Benign | 0.180 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.04 | Neutral | 0.983 | Probably Damaging | 0.602 | Possibly Damaging | 4.25 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2512 | 0.2506 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||||
| c.2101C>G | P701A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these classify the substitution as benign. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX (uncertain) and Foldetta (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 predicts benign, while Foldetta remains uncertain. Based on the collective 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 | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -6.836 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 1.35 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.79 | Ambiguous | -0.16 | Likely Benign | 0.058 | Likely Benign | -0.55 | Neutral | 0.002 | Benign | 0.011 | Benign | 3.50 | Benign | 0.82 | Tolerated | 0.3143 | 0.3765 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| 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.2105A>G | Q702R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q702R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that remain inconclusive are Rosetta, ESM1b, and AlphaMissense‑Default. 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 equal benign and pathogenic signals. Overall, the majority of available predictions lean toward 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. | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | Uncertain | 1 | -7.894 | In-Between | 0.348 | Ambiguous | Likely Benign | -0.31 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.16 | Likely Benign | 0.13 | Likely Benign | 0.294 | Likely Benign | -3.14 | Deleterious | 0.909 | Possibly Damaging | 0.889 | Possibly Damaging | 3.43 | Benign | 0.02 | Affected | 3.47 | 10 | 0.1225 | 0.0605 | 1 | 1 | -1.0 | 28.06 | 270.3 | -52.9 | 0.0 | 0.0 | 0.0 | 0.1 | X | Potentially Pathogenic | The carboxamide side chain of Gln702 is located at the end and outer surface of an α-helix (res. Leu685-Gln702), where it does not directly form hydrogen bonds with any residues in the WT simulations. In the variant simulations, the positively charged guanidinium group of Arg702 forms a salt bridge with the negatively charged carboxylate group of Glu698 on the same helix and/or hydrogen bonds with the backbone carbonyl group of Ala438 on an opposite α-helix (res. Tyr428-Glu436). Consequently, the residue swap could strengthen the tertiary structure assembly, which could have either positive or negative effects on its function. | |||||||||||||||||
| c.2110A>G | S704G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, 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 and polyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors indicate a benign impact, 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 | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -7.827 | In-Between | 0.169 | Likely Benign | Likely Benign | 1.05 | Ambiguous | 0.1 | 1.33 | Ambiguous | 1.19 | Ambiguous | 0.53 | Ambiguous | 0.091 | Likely Benign | -2.25 | Neutral | 0.981 | Probably Damaging | 0.514 | Possibly Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.2224 | 0.3378 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.2111G>A | S704N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704N is listed in ClinVar as benign (ClinVar ID 962301.0) and is present in gnomAD (ID 6‑33441370‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus all report benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the predictions support a benign classification, consistent with the ClinVar status and with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | Benign/Likely benign | 3 | 6-33441370-G-A | 27 | 1.67e-5 | -5.917 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.48 | Likely Benign | 0.1 | -0.12 | Likely Benign | 0.18 | Likely Benign | 0.54 | Ambiguous | 0.058 | Likely Benign | -0.49 | Neutral | 0.771 | Possibly Damaging | 0.275 | Benign | 3.39 | Benign | 0.08 | Tolerated | 3.47 | 10 | 0.0911 | 0.3754 | 1 | 1 | -2.7 | 27.03 | 233.2 | -29.1 | -0.1 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. However, in the variant simulations, the carboxamide side chain of Asn704 achieves more lasting and numerous hydrogen-bonding interactions with the residues at the helix end, such as Glu706, Ala707, and Leu708. Consequently, the residue swap could strengthen the α-helix secondary structure integrity at the helix end, which could have either positive or negative effects on its function. | |||||||||||||
| c.2111G>C | S704T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while FoldX remains inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the aggregate evidence indicates that S704T is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | Uncertain | 1 | -4.930 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.071 | Likely Benign | -1.72 | Neutral | 0.525 | Possibly Damaging | 0.107 | Benign | 3.45 | Benign | 0.07 | Tolerated | 3.47 | 10 | 0.1036 | 0.4674 | 1 | 1 | 0.1 | 14.03 | 201.7 | -18.0 | 0.0 | 0.0 | -0.2 | 0.7 | X | Potentially Benign | Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. Similarly, in the variant simulations, the hydroxyl side chain of Thr704 forms hydrogen bonds with the amide groups of Ala707 and Leu708. Thus, the residue swap does not cause any apparent structural change. | ||||||||||||||||
| c.2113A>C | K705Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K705Q missense variant (ClinVar ID 3699560.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (variant ID 6‑33441372‑A‑C). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (benign)—also yields a benign classification; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence supports a benign impact for K705Q, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | Uncertain | 1 | 6-33441372-A-C | 1 | 6.20e-7 | -5.787 | Likely Benign | 0.436 | Ambiguous | Likely Benign | -0.10 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.12 | Likely Benign | -0.02 | Likely Benign | 0.142 | Likely Benign | -0.24 | Neutral | 0.997 | Probably Damaging | 0.969 | Probably Damaging | 3.42 | Benign | 0.78 | Tolerated | 3.47 | 10 | 0.3063 | 0.1014 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||
| c.2115G>C | K705N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K705N is listed in ClinVar (ID 872011.0) as Pathogenic and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, Rosetta, premPS, FATHMM) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default). Uncertain results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic, and Foldetta also yields an uncertain stability change. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which aligns 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 Pathogenic | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | Likely Pathogenic | 1 | -9.767 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.56 | Ambiguous | 0.44 | Likely Benign | 0.183 | Likely Benign | -3.12 | Deleterious | 0.996 | Probably Damaging | 0.876 | Possibly Damaging | 3.37 | Benign | 0.02 | Affected | 3.47 | 10 | 0.2480 | 0.1124 | 1 | 0 | 0.4 | -14.07 | 221.4 | -20.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Uncertain | The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||
| c.2115G>T | K705N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K705N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further support a pathogenic interpretation: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic”; AlphaMissense‑Optimized remains uncertain, and Foldetta is also uncertain. Overall, the balance of evidence favors a pathogenic effect for K705N, and this conclusion 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. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | -9.767 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.0 | 0.37 | Likely Benign | 0.56 | Ambiguous | 0.44 | Likely Benign | 0.183 | Likely Benign | -3.12 | Deleterious | 0.996 | Probably Damaging | 0.876 | Possibly Damaging | 3.37 | Benign | 0.02 | Affected | 3.47 | 10 | 0.2480 | 0.1124 | 1 | 0 | 0.4 | -14.07 | 221.4 | -20.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Uncertain | The amino side chain of Lys705, located at the end and outer surface of an α-helix (res. Thr704-Gly712), does not form any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Asn705 briefly forms a salt bridge with Glu706. However, there is no apparent difference between the systems. Due to the model ending abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||||
| c.2119G>C | A707P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A707P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions come from Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. 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) as 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. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -8.082 | Likely Pathogenic | 0.885 | Likely Pathogenic | Ambiguous | 0.28 | Likely Benign | 0.1 | 5.75 | Destabilizing | 3.02 | Destabilizing | 0.76 | Ambiguous | 0.228 | Likely Benign | -2.92 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.41 | Benign | 0.09 | Tolerated | 0.1375 | 0.3095 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2119G>T | A707S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A707S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign impact, 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 | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -4.432 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.70 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.67 | Ambiguous | 0.28 | Likely Benign | 0.150 | Likely Benign | -1.07 | Neutral | 0.848 | Possibly Damaging | 0.945 | Probably Damaging | 3.43 | Benign | 0.08 | Tolerated | 0.1825 | 0.2924 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.211G>C | D71H 2D AIThe SynGAP1 D71H 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, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, 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 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 | 0.575842 | Disordered | 0.456046 | Uncertain | 0.350 | 0.799 | 0.375 | -3.974 | Likely Benign | 0.653 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -1.66 | Neutral | 0.637 | Possibly Damaging | 0.136 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1655 | 0.6446 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2120C>G | A707G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give uncertain or inconclusive results and are treated as unavailable evidence. 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 remains uncertain. Overall, the majority of definitive predictions lean toward a benign effect, and there is no ClinVar status 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. | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -7.480 | In-Between | 0.224 | Likely Benign | Likely Benign | 1.45 | Ambiguous | 0.0 | 1.52 | Ambiguous | 1.49 | Ambiguous | 0.62 | Ambiguous | 0.198 | Likely Benign | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.960 | Probably Damaging | 3.42 | Benign | 0.01 | Affected | 0.1678 | 0.2388 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.2128A>C | K710Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K710Q missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The high‑accuracy AlphaMissense‑Optimized score classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic)—indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the majority of evidence points to a benign 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. | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -8.920 | Likely Pathogenic | 0.372 | Ambiguous | Likely Benign | 0.12 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.07 | Likely Benign | 0.49 | Likely Benign | 0.183 | Likely Benign | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3043 | 0.1214 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.2130G>C | K710N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K710N 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 PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or unavailable results are reported for FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic impact for K710N, 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 | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -9.330 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 0.50 | Ambiguous | 0.68 | Ambiguous | 0.33 | Likely Benign | 0.201 | Likely Benign | -4.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.2485 | 0.1124 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.2130G>T | K710N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K710N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. In contrast, a majority of algorithms predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, 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, and this conclusion does not conflict with 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 | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -9.330 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 0.50 | Ambiguous | 0.68 | Ambiguous | 0.33 | Likely Benign | 0.201 | Likely Benign | -4.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 0.2485 | 0.1124 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.2131C>G | L711V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L711V is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441596‑C‑G). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. The majority of other in silico predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, 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. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | Uncertain | 1 | 6-33441596-C-G | 1 | 6.20e-7 | -10.045 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 3.48 | Destabilizing | 0.1 | 2.22 | Destabilizing | 2.85 | Destabilizing | 1.40 | Destabilizing | 0.170 | Likely Benign | -2.59 | Deleterious | 0.992 | Probably Damaging | 0.970 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 3.50 | 9 | 0.1318 | 0.3010 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||
| c.2134G>A | G712S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Uncertain results come from premPS, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of evidence points to a pathogenic effect for G712S. This conclusion does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -7.942 | In-Between | 0.422 | Ambiguous | Likely Benign | 2.30 | Destabilizing | 0.1 | 4.79 | Destabilizing | 3.55 | Destabilizing | 0.62 | Ambiguous | 0.282 | Likely Benign | -4.84 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.02 | Affected | 0.2862 | 0.4501 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||
| c.2135G>C | G712A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G712A missense variant 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, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Two tools report uncertainty: premPS and AlphaMissense‑Default. High‑accuracy assessments further refine the picture. AlphaMissense‑Optimized classifies the variant as benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict (2 benign vs. 1 pathogenic vote). Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Because the majority of conventional predictors (7/11) indicate pathogenicity, the overall consensus leans toward a pathogenic impact, despite the mixed high‑accuracy results. 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. | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -6.444 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 2.89 | Destabilizing | 0.1 | 4.98 | Destabilizing | 3.94 | Destabilizing | 0.70 | Ambiguous | 0.281 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.44 | Benign | 0.02 | Affected | 0.3993 | 0.4105 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.2137C>G | P713A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P713A is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus score is labeled Likely Pathogenic. FoldX, Foldetta, and premPS give uncertain results. High‑accuracy tools: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with 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 | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -8.535 | Likely Pathogenic | 0.689 | Likely Pathogenic | Likely Benign | 1.04 | Ambiguous | 0.1 | 0.15 | Likely Benign | 0.60 | Ambiguous | 0.75 | Ambiguous | 0.235 | Likely Benign | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | 0.3159 | 0.3475 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.2137C>T | P713S 2D AIThe SynGAP1 missense variant P713S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are provided by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this ambiguity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates a likely pathogenic effect, and Foldetta likewise yields an uncertain stability change. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns 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 | GAP | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -8.496 | Likely Pathogenic | 0.846 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.7 | 0.19 | Likely Benign | 0.55 | Ambiguous | 0.62 | Ambiguous | 0.261 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.3234 | 0.3674 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.2143C>G | P715A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715A has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by FoldX, 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 classified as Likely Pathogenic. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts Benign, whereas the SGM‑Consensus remains Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -9.261 | Likely Pathogenic | 0.597 | Likely Pathogenic | Likely Benign | 2.69 | Destabilizing | 0.0 | 0.28 | Likely Benign | 1.49 | Ambiguous | 0.77 | Ambiguous | 0.229 | Likely Benign | -7.13 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 0.2993 | 0.3560 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.2143C>T | P715S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715S is listed in ClinVar as pathogenic (ClinVar ID 1804065.0) and is present in gnomAD (ID 6‑33441608‑C‑T). Functional prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Predictions that are inconclusive are Rosetta, premPS, ESM1b, and AlphaMissense‑Optimized. 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. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | Likely Pathogenic | 1 | 6-33441608-C-T | 1 | 6.20e-7 | -7.635 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 3.54 | Destabilizing | 0.0 | 0.81 | Ambiguous | 2.18 | Destabilizing | 0.94 | Ambiguous | 0.277 | Likely Benign | -7.17 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.43 | Benign | 0.01 | Affected | 3.50 | 9 | 0.2977 | 0.3755 | 1 | -1 | 0.8 | -10.04 | 231.8 | -14.0 | -0.1 | 0.0 | -0.8 | 0.1 | X | Uncertain | Pro715, along with Gly712 and Pro713, are located in a hinge region of an α-helix making a ~90-degree turn (res. Lys705-Leu725). In the WT simulations, the pyrrolidine side chain of Pro715, lacking the backbone amide groups altogether, forces the tight helix turn to take place while also hydrophobically packing with nearby residues (e.g., Leu700, Leu708, Leu714, and Leu718). Leu715, with a normal amide backbone, could potentially affect protein folding and turn formation, although this was not observed in the variant simulations. Additionally, the hydroxyl group of the Ser715 side chain can form hydrogen bonds with the backbone carbonyl group of Gly712 and disrupt the hydrophobic packing arrangement of the leucine residues from the neighboring α-helices, impacting the GAP domain tertiary assembly. | ||||||||||||||
| c.2147G>A | R716Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716Q is listed in ClinVar with an uncertain significance (ClinVar ID 411585.0) and is present in gnomAD (ID 6‑33441612‑G‑A). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b, while premPS is inconclusive. 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. Overall, the balance of evidence leans toward 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. | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | Conflicting | 2 | 6-33441612-G-A | 4 | 2.48e-6 | -8.338 | Likely Pathogenic | 0.308 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.47 | Likely Benign | 0.23 | Likely Benign | 0.58 | Ambiguous | 0.210 | Likely Benign | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.50 | 9 | 0.2834 | 0.2180 | 1 | 1 | 1.0 | -28.06 | 250.0 | 48.9 | 0.0 | 0.0 | -0.5 | 0.0 | X | Uncertain | The guanidinium group of Arg716, located on the outer surface of an α-helix (res. Leu714-Arg726), forms a salt bridge with the carboxylate group of Asp720. In the variant simulations, the carboxamide group of Gln716 also forms a hydrogen bond with the carboxylate group of Asp720, although this bond is weaker than the Arg716 salt bridge in the WT. Overall, no adverse effects on the protein structure are observed in the simulations. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||
| c.2156A>G | N719S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719S is reported in gnomAD (variant ID 6‑33441621‑A‑G) but has no ClinVar entry. Prediction tools that uniformly indicate 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. 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 status: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus itself is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Benign. Overall, the preponderance of evidence indicates that 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 | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | 6-33441621-A-G | 2 | 1.24e-6 | -5.190 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.06 | Likely Benign | 0.0 | -0.29 | Likely Benign | -0.18 | Likely Benign | 0.46 | Likely Benign | 0.087 | Likely Benign | -1.83 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.85 | Benign | 0.40 | Tolerated | 3.50 | 9 | 0.2611 | 0.4653 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||
| c.2157C>A | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, ESM1b, and Foldetta) give 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 impact, and this conclusion 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. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.250 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2157C>G | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect, whereas polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. FoldX, Rosetta, ESM1b, and Foldetta are inconclusive. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign outcome; Foldetta remains uncertain. Consequently, the variant is most likely benign, 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. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.244 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2158G>A | D720N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D720N is listed in ClinVar as benign (ClinVar ID 2837618.0) and is present in gnomAD (ID 6‑33441623‑G‑A). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. With seven pathogenic versus six benign predictions overall, the variant is most likely pathogenic according to in‑silico evidence, which contradicts the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | Likely Benign | 1 | 6-33441623-G-A | 5 | 3.10e-6 | -9.135 | Likely Pathogenic | 0.654 | Likely Pathogenic | Likely Benign | 0.01 | Likely Benign | 0.0 | -0.20 | Likely Benign | -0.10 | Likely Benign | 0.46 | Likely Benign | 0.289 | Likely Benign | -3.74 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.18 | Pathogenic | 0.01 | Affected | 3.50 | 9 | 0.1216 | 0.5513 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||
| c.2158G>C | D720H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720H missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is labeled Likely Pathogenic. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, indicates a Benign effect. Considering the overall distribution of predictions, 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 | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -12.355 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | -0.87 | Ambiguous | -0.42 | Likely Benign | 0.48 | Likely Benign | 0.444 | Likely Benign | -5.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.13 | Pathogenic | 0.01 | Affected | 0.1363 | 0.6198 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.2159A>G | D720G 2D AISynGAP1 missense variant D720G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools remain inconclusive: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. 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 | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -11.130 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.4 | 0.53 | Ambiguous | 0.49 | Likely Benign | 0.46 | Likely Benign | 0.427 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.15 | Pathogenic | 0.01 | Affected | 0.4027 | 0.5011 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.215G>A | R72Q 2D AIThe SynGAP1 missense variant R72Q is reported in gnomAD (variant ID 6-33425823‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: 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 evidence points to a benign effect for R72Q, 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 | 6-33425823-G-A | -4.413 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.13 | Neutral | 0.829 | Possibly Damaging | 0.238 | Benign | 4.20 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3570 | 0.2380 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||||||
| c.2161A>T | I721F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact, while premPS remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -12.559 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 4.61 | Destabilizing | 0.1 | 2.74 | Destabilizing | 3.68 | Destabilizing | 0.66 | Ambiguous | 0.295 | Likely Benign | -3.74 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0420 | 0.2931 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2165G>A | S722N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect. No tool predicts pathogenicity; the only inconclusive results come from premPS and AlphaMissense‑Default, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Taken together, the evidence overwhelmingly supports a benign classification, 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 | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -4.399 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.17 | Likely Benign | 0.79 | Ambiguous | 0.051 | Likely Benign | -0.91 | Neutral | 0.072 | Benign | 0.028 | Benign | 2.58 | Benign | 0.27 | Tolerated | 0.1258 | 0.3452 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.2165G>C | S722T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722T is reported in gnomAD (6‑33441630‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while FoldX is uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441630-G-C | 1 | 6.20e-7 | -5.734 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | -0.32 | Likely Benign | 0.11 | Likely Benign | -0.12 | Likely Benign | 0.118 | Likely Benign | -0.57 | Neutral | 0.921 | Possibly Damaging | 0.414 | Benign | 2.57 | Benign | 1.00 | Tolerated | 3.50 | 8 | 0.1357 | 0.4363 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||
| c.2167A>G | T723A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: SIFT, PolyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, REVEL, and the protein‑stability predictors FoldX, Rosetta, premPS, and Foldetta all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Based on the uniform predictions, the variant is most likely benign, 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 Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -4.572 | Likely Benign | 0.064 | Likely Benign | Likely Benign | -0.47 | Likely Benign | 0.0 | 0.16 | Likely Benign | -0.16 | Likely Benign | 0.25 | Likely Benign | 0.053 | Likely Benign | -0.91 | Neutral | 0.161 | Benign | 0.045 | Benign | 3.51 | Benign | 0.06 | Tolerated | 0.3902 | 0.3639 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.2167A>T | T723S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The high‑accuracy consensus methods confirm the benign assessment: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the majority of evidence supports a benign impact for T723S, 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 | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -4.792 | Likely Benign | 0.091 | Likely Benign | Likely Benign | -0.26 | Likely Benign | 0.0 | 0.28 | Likely Benign | 0.01 | Likely Benign | 0.23 | Likely Benign | 0.037 | Likely Benign | -0.89 | Neutral | 0.673 | Possibly Damaging | 0.678 | Possibly Damaging | 3.55 | Benign | 0.06 | Tolerated | 0.3171 | 0.3731 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2170G>A | A724T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724T missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Predictions that are inconclusive are AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) suggest a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, as there is no existing classification to contradict. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -8.047 | Likely Pathogenic | 0.456 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.1 | 1.10 | Ambiguous | 1.03 | Ambiguous | 0.40 | Likely Benign | 0.273 | Likely Benign | -2.87 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.09 | Pathogenic | 0.01 | Affected | 0.1149 | 0.5897 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2170G>C | A724P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A724P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: REVEL predicts a benign effect, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS [uncertain], PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, classifies the variant as pathogenic. No tool suggests a benign outcome, and the single benign prediction (REVEL) is outweighed by the consensus of pathogenic predictions. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -12.817 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.3 | 6.35 | Destabilizing | 4.63 | Destabilizing | 0.52 | Ambiguous | 0.391 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.04 | Pathogenic | 0.04 | Affected | 0.1642 | 0.4273 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2170G>T | A724S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724S is not reported in ClinVar and is absent from gnomAD. 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. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. 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, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points to a benign impact for A724S, 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 | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -6.893 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.93 | Ambiguous | 0.1 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.57 | Ambiguous | 0.265 | Likely Benign | -1.68 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | 2.20 | Pathogenic | 0.25 | Tolerated | 0.2308 | 0.4518 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2171C>G | A724G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A724G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -8.908 | Likely Pathogenic | 0.580 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.1 | 1.73 | Ambiguous | 1.59 | Ambiguous | 0.56 | Ambiguous | 0.286 | Likely Benign | -3.10 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.07 | Pathogenic | 0.08 | Tolerated | 0.2001 | 0.3609 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.2180A>G | N727S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N727S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. 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 majority of evidence supports a benign effect. 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. | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | -6.195 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.28 | Likely Benign | 0.30 | Likely Benign | 0.18 | Likely Benign | 0.118 | Likely Benign | -2.67 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.19 | Pathogenic | 0.23 | Tolerated | 0.3833 | 0.6680 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||
| c.2182C>G | P728A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728A 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, whereas the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence from multiple in silico tools indicates that the variant is most likely pathogenic, and this conclusion 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 | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -9.350 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 0.78 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.79 | Ambiguous | 0.69 | Ambiguous | 0.277 | Likely Benign | -6.59 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 0.3568 | 0.3148 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.2186A>G | N729S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729S 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus also as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | Uncertain | 1 | -1.578 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.14 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.74 | Ambiguous | -0.36 | Likely Benign | 0.063 | Likely Benign | -0.42 | Neutral | 0.221 | Benign | 0.027 | Benign | 3.38 | Benign | 0.93 | Tolerated | 3.59 | 7 | 0.3411 | 0.4854 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||
| c.2187C>A | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2187C>G | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2188A>T | I730F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I730F has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or tolerated. Only polyPhen2_HumDiv classifies the change as pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a benign effect. No prediction tool or stability analysis is inconclusive. Based on the collective evidence, the variant is most likely benign, and 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 | 0.733139 | Disordered | 0.420109 | Uncertain | 0.591 | 0.619 | 0.750 | -4.953 | Likely Benign | 0.173 | Likely Benign | Likely Benign | -0.54 | Ambiguous | 0.1 | -0.01 | Likely Benign | -0.28 | Likely Benign | -0.01 | Likely Benign | 0.055 | Likely Benign | -1.86 | Neutral | 0.699 | Possibly Damaging | 0.152 | Benign | 3.45 | Benign | 0.08 | Tolerated | 0.0509 | 0.2082 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||
| c.2191C>A | Q731K 2D AIThe SynGAP1 missense variant Q731K 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while 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, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of evidence from both general and 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 | 0.750527 | Disordered | 0.415202 | Uncertain | 0.507 | 0.654 | 0.750 | -6.686 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.58 | Neutral | 0.490 | Possibly Damaging | 0.149 | Benign | 2.67 | Benign | 0.20 | Tolerated | 0.1998 | 0.3932 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2192A>G | Q731R 2D AIThe SynGAP1 missense variant Q731R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and 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. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, 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 | 0.750527 | Disordered | 0.415202 | Uncertain | 0.507 | 0.654 | 0.750 | -5.873 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -1.63 | Neutral | 0.604 | Possibly Damaging | 0.293 | Benign | 2.66 | Benign | 0.14 | Tolerated | 0.1571 | 0.1775 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2197C>A | Q733K 2D AIThe SynGAP1 missense variant Q733K 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, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q733K, 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 | -6.779 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.66 | Neutral | 0.797 | Possibly Damaging | 0.312 | Benign | 2.61 | Benign | 0.05 | Affected | 0.1572 | 0.2790 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2198A>G | Q733R 2D AIThe SynGAP1 missense variant Q733R 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 for Q733R, 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 | -5.986 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.96 | Neutral | 0.950 | Possibly Damaging | 0.612 | Possibly Damaging | 2.57 | Benign | 0.04 | Affected | 0.1419 | 0.1279 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2200C>G | P734A 2D AIThe SynGAP1 missense variant P734A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect. Consensus predictors such as SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and high‑accuracy methods including AlphaMissense‑Optimized all classify the variant as benign. Additional in silico assessments—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—also predict a benign outcome. No tool in the dataset suggests pathogenicity. Protein‑stability analysis via Foldetta is unavailable for this variant. Based on the collective evidence, the variant is most likely benign, 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -3.907 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -2.19 | Neutral | 0.022 | Benign | 0.074 | Benign | 2.74 | Benign | 0.24 | Tolerated | 0.3801 | 0.3306 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2200C>T | P734S 2D AIThe SynGAP1 missense variant P734S is listed in ClinVar with an uncertain significance (ClinVar ID 2283225.0) and is present in the gnomAD database (gnomAD ID 6‑33441665‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this benign assessment: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | Uncertain | 2 | 6-33441665-C-T | 2 | 1.24e-6 | -4.291 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -2.44 | Neutral | 0.344 | Benign | 0.048 | Benign | 2.77 | Benign | 0.11 | Tolerated | 3.64 | 6 | 0.3775 | 0.3650 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| 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.2204G>A | S735N 2D AIThe SynGAP1 missense variant S735N is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, 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 | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.697 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.68 | Neutral | 0.400 | Benign | 0.138 | Benign | 2.65 | Benign | 0.18 | Tolerated | 0.1375 | 0.3827 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2209C>A | Q737K 2D AIThe SynGAP1 missense variant Q737K 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate 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 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. Taken together, the majority of evidence points to a benign effect for Q737K, 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -5.841 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.16 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.77 | Benign | 0.07 | Tolerated | 0.2081 | 0.4009 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.220A>G | S74G 2D AIThe SynGAP1 missense variant S74G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 effect. The variant is most likely benign, and this conclusion 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 | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | -3.540 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -1.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.08 | Benign | 0.00 | Affected | 0.2347 | 0.3749 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2212A>G | S738G 2D AIThe SynGAP1 missense variant S738G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates 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. 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 | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -3.863 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.53 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.66 | Benign | 0.01 | Affected | 0.2032 | 0.3385 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2213G>A | S738N 2D AIThe SynGAP1 missense variant S738N is reported in ClinVar as having no entry and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority vote, matching the SGM‑Consensus label of “Likely Benign.” 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 benign impact, and this assessment 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 | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -5.005 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.53 | Neutral | 0.425 | Benign | 0.233 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1284 | 0.3251 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2213G>C | S738T 2D AIThe SynGAP1 missense variant S738T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that 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 | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -3.926 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.68 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.73 | Benign | 0.51 | Tolerated | 0.1336 | 0.4227 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2219G>A | R740Q 2D AIThe SynGAP1 missense variant R740Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441684‑G‑A). 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 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 a benign interpretation: 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 reported result for this variant, so it does not influence the assessment. Overall, the majority of predictions indicate that R740Q is most likely benign, 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 | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | Uncertain | 1 | 6-33441684-G-A | 4 | 2.48e-6 | -5.195 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.67 | Neutral | 0.999 | Probably Damaging | 0.881 | Possibly Damaging | 2.60 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.3454 | 0.2203 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.221G>A | S74N 2D AIThe SynGAP1 missense variant S74N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33425829‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: 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 computational evidence indicates that 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 | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | Uncertain | 1 | 6-33425829-G-A | 5 | 3.10e-6 | -5.156 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.89 | Neutral | 0.043 | Benign | 0.007 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1434 | 0.4193 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
| c.221G>C | S74T 2D AIThe SynGAP1 missense variant S74T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion 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 Benign | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | -3.874 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.53 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.22 | Benign | 0.00 | Affected | 0.1573 | 0.4704 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2221C>G | P741A 2D AIThe SynGAP1 missense variant P741A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” while Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, 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 | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -3.995 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.33 | Neutral | 0.425 | Benign | 0.136 | Benign | 3.01 | Benign | 0.98 | Tolerated | 0.2942 | 0.3883 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2221C>T | P741S 2D AIThe SynGAP1 missense variant P741S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441686‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic one. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability data are available, so it does not influence the conclusion. Overall, the computational evidence indicates that the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | Uncertain | 2 | 6-33441686-C-T | 3 | 1.86e-6 | -3.700 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.92 | Benign | 0.00 | Affected | 4.32 | 2 | 0.2888 | 0.4278 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2225G>A | R742Q 2D AIThe SynGAP1 missense variant R742Q is listed in ClinVar (ID 928481.0) with an uncertain significance annotation and is observed in gnomAD (variant ID 6‑33441690‑G‑A). Consensus from multiple in‑silico predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—uniformly classify the change as benign. No tool in the dataset reports a pathogenic prediction. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. A protein‑folding stability analysis via Foldetta is not available for this variant. Overall, the computational evidence strongly favors a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. The variant is most likely benign, and this assessment does not contradict its ClinVar status. 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 | 2 | 6-33441690-G-A | 24 | 1.49e-5 | -4.090 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.19 | Neutral | 0.032 | Benign | 0.007 | Benign | 2.73 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.3660 | 0.1530 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2227C>G | P743A 2D AIThe SynGAP1 missense variant P743A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and 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 | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -4.253 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.10 | Neutral | 0.005 | Benign | 0.008 | Benign | 2.78 | Benign | 0.12 | Tolerated | 0.3158 | 0.3604 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2230C>A | Q744K 2D AIThe SynGAP1 missense variant Q744K is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Based on the collective predictions, the variant 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -3.929 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.22 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.79 | Benign | 0.07 | Tolerated | 0.1784 | 0.3757 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2231A>G | Q744R 2D AIThe SynGAP1 missense variant Q744R 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 unavailable. Overall, the majority of evidence indicates that 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -2.207 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.80 | Benign | 0.05 | Affected | 0.1437 | 0.1588 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2233C>G | P745A 2D AIThe SynGAP1 missense variant P745A 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. 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 P745A, 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 | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -4.599 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -2.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.55 | Benign | 0.17 | Tolerated | 0.3424 | 0.3458 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2236G>C | V746L 2D AIThe SynGAP1 missense variant V746L is catalogued in gnomAD (ID 6‑33441701‑G‑C) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available for this variant. Taken together, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | 6-33441701-G-C | 1 | 6.19e-7 | -3.260 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.0896 | 0.5065 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2236G>T | V746L 2D AIThe SynGAP1 missense variant V746L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that V746L is most likely benign, 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -3.260 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.0896 | 0.5065 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2246G>A | R749Q 2D AIThe SynGAP1 missense variant R749Q is listed in ClinVar (ID 793884.0) as Benign and is present in gnomAD (6‑33441711‑G‑A). 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports 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—including high‑accuracy predictions—supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441711-G-A | 4 | 2.48e-6 | -3.069 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.00 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 2 | 0.3467 | 0.2529 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2249G>C | G750A 2D AIThe SynGAP1 missense variant G750A 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 not available. Based on the collective 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 | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.263 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.65 | Neutral | 0.996 | Probably Damaging | 0.887 | Possibly Damaging | 2.52 | Benign | 0.04 | Affected | 0.3683 | 0.4792 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2251C>G | P751A 2D AIThe SynGAP1 missense variant P751A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -4.612 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.42 | Neutral | 0.028 | Benign | 0.009 | Benign | 2.73 | Benign | 0.26 | Tolerated | 0.3592 | 0.5487 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2251C>T | P751S 2D AIThe SynGAP1 missense variant P751S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely 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 tools and the high‑accuracy predictions indicate that P751S is most likely benign, 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -4.157 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.80 | Neutral | 0.514 | Possibly Damaging | 0.216 | Benign | 2.70 | Benign | 0.33 | Tolerated | 0.3446 | 0.5837 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>A | S752T 2D AIThe SynGAP1 missense variant S752T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. 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 effect, and this conclusion does not contradict the lack of ClinVar annotation. 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 | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -4.040 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.33 | Neutral | 0.248 | Benign | 0.137 | Benign | 1.55 | Pathogenic | 0.07 | Tolerated | 0.1633 | 0.6342 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>C | S752P 2D AIThe SynGAP1 missense variant S752P is not reported in ClinVar and is absent from gnomAD. 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 stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S752P, and this conclusion does not contradict the ClinVar status, 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 | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -3.491 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -1.09 | Neutral | 0.998 | Probably Damaging | 0.912 | Probably Damaging | 1.51 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5882 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>G | S752A 2D AIThe SynGAP1 missense variant S752A has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, 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 FATHMM. 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 | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -3.258 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.42 | Neutral | 0.910 | Possibly Damaging | 0.524 | Possibly Damaging | 1.59 | Pathogenic | 0.04 | Affected | 0.5092 | 0.5634 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2257G>C | A753P 2D AIThe SynGAP1 missense variant A753P 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, 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 Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -2.486 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.05 | Neutral | 0.966 | Probably Damaging | 0.575 | Possibly Damaging | 2.59 | Benign | 0.30 | Tolerated | 0.2143 | 0.5442 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2257G>T | A753S 2D AIThe SynGAP1 missense variant A753S is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -3.656 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.25 | Neutral | 0.062 | Benign | 0.015 | Benign | 3.03 | Benign | 0.59 | Tolerated | 0.2905 | 0.5899 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2258C>G | A753G 2D AIThe SynGAP1 missense variant A753G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. 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 not available, 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 status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -4.257 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.10 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 2.62 | Benign | 0.65 | Tolerated | 0.2447 | 0.5089 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2266C>A | Q756K 2D AIThe SynGAP1 missense variant Q756K 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 for Q756K, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -6.059 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -1.47 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.60 | Pathogenic | 0.21 | Tolerated | 0.1816 | 0.4797 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>G | Q756R 2D AIThe SynGAP1 missense variant Q756R 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 (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 for Q756R, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -5.044 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -1.77 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.58 | Pathogenic | 0.14 | Tolerated | 0.1500 | 0.2440 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>A | G757S 2D AIThe SynGAP1 missense variant G757S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -1.492 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.47 | Neutral | 0.007 | Benign | 0.008 | Benign | 2.73 | Benign | 0.29 | Tolerated | 0.2595 | 0.3877 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.226T>A | S76T 2D AIThe SynGAP1 missense variant S76T 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 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 | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | -4.000 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.73 | Neutral | 0.805 | Possibly Damaging | 0.483 | Possibly Damaging | 3.78 | Benign | 0.00 | Affected | 0.1117 | 0.4774 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.226T>C | S76P 2D AIThe SynGAP1 missense variant S76P 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 points to a benign effect for S76P, 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 | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | -3.833 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.64 | Neutral | 0.909 | Possibly Damaging | 0.665 | Possibly Damaging | 3.77 | Benign | 0.00 | Affected | 0.1790 | 0.4138 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.226T>G | S76A 2D AIThe SynGAP1 missense variant S76A is reported in gnomAD (ID 6‑33425834‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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 unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | 6-33425834-T-G | 1 | 6.20e-7 | -3.230 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.10 | Neutral | 0.643 | Possibly Damaging | 0.277 | Benign | 3.86 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4543 | 0.3619 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.2270G>A | G757D 2D AIThe SynGAP1 missense variant G757D is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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. Taken together, the preponderance of evidence supports a benign interpretation, and this assessment does not contradict any ClinVar annotation (none is present). Therefore, the variant is most likely benign, with no conflict with ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -4.613 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -0.90 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.11 | Tolerated | 0.1826 | 0.1611 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2270G>C | G757A 2D AIThe SynGAP1 missense change G757A is catalogued in ClinVar (ID 3635272.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction algorithms uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool in the dataset predicts pathogenicity. High‑accuracy consensus methods corroborate this view: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect, and AlphaMissense‑Optimized also predicts benign. The Foldetta stability assessment is unavailable for this variant. Taken together, the evidence overwhelmingly supports a benign interpretation, 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 | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | Uncertain | 1 | -2.626 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.45 | Neutral | 0.267 | Benign | 0.127 | Benign | 2.73 | Benign | 0.35 | Tolerated | 0.3690 | 0.3842 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2275A>G | M759V 2D AIThe SynGAP1 missense variant M759V is catalogued in gnomAD (ID 6‑33441740‑A‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available for this variant. Taken together, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | 6-33441740-A-G | 20 | 1.24e-5 | -3.985 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.00 | Neutral | 0.267 | Benign | 0.127 | Benign | 2.67 | Benign | 0.23 | Tolerated | 3.99 | 5 | 0.2926 | 0.3041 | 1 | 2 | 2.3 | -32.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.2277G>A | M759I 2D AIThe SynGAP1 missense variant M759I is listed in ClinVar (ID 3686687.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441742‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while 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 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | 6-33441742-G-A | 1 | 6.20e-7 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2277G>C | M759I 2D AIThe SynGAP1 missense variant M759I is catalogued in gnomAD (6‑33441742‑G‑C) and has no ClinVar entry. Consensus from multiple in‑silico predictors points to a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the variant as benign, while only polyPhen‑2 HumDiv flags it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | 6-33441742-G-C | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.2277G>T | M759I 2D AIThe SynGAP1 missense variant M759I 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools points to a benign impact for M759I, 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2282G>A | R761Q 2D AIThe SynGAP1 missense variant R761Q is listed in ClinVar (ID 2882770.0) with an “Uncertain” status and is present in gnomAD (6‑33441747‑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 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 the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | Uncertain | 1 | 6-33441747-G-A | 11 | 6.81e-6 | -4.187 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -0.63 | Neutral | 0.996 | Probably Damaging | 0.878 | Possibly Damaging | 2.75 | Benign | 0.40 | Tolerated | 3.99 | 5 | 0.2640 | 0.2329 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2284G>C | D762H 2D AIThe SynGAP1 D762H missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. 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—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available 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 classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.643 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -2.73 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.08 | Pathogenic | 0.02 | Affected | 0.2007 | 0.9102 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2285A>G | D762G 2D AIThe SynGAP1 missense variant D762G 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 ESM1b, whereas those that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the majority of predictions and the SGM‑Consensus outcome, 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 | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -1.062 | Likely Benign | 0.812 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.55 | Deleterious | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 2.10 | Pathogenic | 0.08 | Tolerated | 0.4710 | 0.7841 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2290A>C | N764H 2D  AIThe SynGAP1 missense variant N764H is reported in gnomAD (ID 6‑33441755‑A‑C) but has no ClinVar entry. 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 made 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. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar classification (none is present). 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 | 6-33441755-A-C | -4.954 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -2.09 | Neutral | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 2.59 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1236 | 0.5056 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||
| 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.2292C>A | N764K 2D AIThe SynGAP1 missense variant N764K is not reported in ClinVar and has no entries 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 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 classification, 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. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.867 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.073 | Likely Benign | -1.36 | Neutral | 0.992 | Probably Damaging | 0.921 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.2005 | 0.3539 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2292C>G | N764K 2D AIThe SynGAP1 missense variant N764K is not reported in ClinVar and has no entries 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 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 classification, 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. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.867 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.073 | Likely Benign | -1.36 | Neutral | 0.992 | Probably Damaging | 0.921 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.2005 | 0.3539 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2293A>G | S765G 2D AIThe SynGAP1 missense variant S765G 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 result is available, so it does not influence the 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 | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -4.658 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.98 | Neutral | 0.963 | Probably Damaging | 0.950 | Probably Damaging | 4.09 | Benign | 0.05 | Affected | 0.2894 | 0.4946 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2294G>A | S765N 2D AIThe SynGAP1 missense variant S765N (ClinVar ID 2979632.0) is listed as “Uncertain” in ClinVar and is not reported 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). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, 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 | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | Uncertain | 1 | -5.098 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 0.094 | Likely Benign | -0.94 | Neutral | 0.985 | Probably Damaging | 0.950 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 3.64 | 6 | 0.1141 | 0.4658 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.2294G>C | S765T 2D AIThe SynGAP1 missense variant S765T 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 predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -4.233 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -1.12 | Neutral | 0.963 | Probably Damaging | 0.950 | Probably Damaging | 4.13 | Benign | 0.37 | Tolerated | 0.1312 | 0.6673 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>A | S766T 2D AIThe SynGAP1 missense variant S766T 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, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -4.923 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.25 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1461 | 0.6511 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>G | S766A 2D AIThe SynGAP1 missense variant S766A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 effect. 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -6.115 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.98 | Neutral | 0.447 | Benign | 0.198 | Benign | 4.17 | Benign | 0.02 | Affected | 0.5059 | 0.5705 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2299A>T | I767F 2D AIThe SynGAP1 missense variant I767F is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion 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 | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | -3.618 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -1.37 | Neutral | 0.003 | Benign | 0.002 | Benign | 4.04 | Benign | 0.06 | Tolerated | 0.0643 | 0.3567 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.22A>T | I8F 2D AIThe SynGAP1 missense variant I8F 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 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 | 0.490133 | Structured | 0.543080 | Binding | 0.341 | 0.916 | 0.625 | -3.000 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.02 | Benign | 0.00 | Affected | 0.0483 | 0.2871 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2302G>A | D768N 2D AIThe SynGAP1 missense variant D768N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442460‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | Uncertain | 1 | 6-33442460-G-A | 2 | 2.57e-6 | -6.892 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.048 | Likely Benign | -0.77 | Neutral | 0.106 | Benign | 0.009 | Benign | 4.07 | Benign | 0.96 | Tolerated | 3.64 | 6 | 0.1178 | 0.7843 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||
| 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.2303A>G | D768G 2D AIThe SynGAP1 D768G missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all predict benign, whereas AlphaMissense‑Default predicts pathogenic. The high‑accuracy AlphaMissense‑Optimized result is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, which would provide a protein‑folding stability assessment, has no available output for this variant. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar entry. 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 | -7.150 | In-Between | 0.697 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.03 | Neutral | 0.393 | Benign | 0.131 | Benign | 4.09 | Benign | 0.72 | Tolerated | 0.4130 | 0.7476 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2308C>A | Q770K 2D AIThe SynGAP1 missense variant Q770K 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. 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 | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.768 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -0.72 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.20 | Benign | 0.14 | Tolerated | 0.1984 | 0.4737 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>G | Q770R 2D AIThe SynGAP1 missense variant Q770R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is 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, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the collective evidence strongly suggests that 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -3.873 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -1.38 | Neutral | 0.194 | Benign | 0.071 | Benign | 4.14 | Benign | 0.07 | Tolerated | 0.1610 | 0.2580 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.230G>A | S77N 2D AIThe SynGAP1 missense variant S77N 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 preponderance of 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -4.597 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.78 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 0.1088 | 0.3774 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.230G>C | S77T 2D AIThe SynGAP1 missense variant S77T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates 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 not available, so they do not influence the assessment. Overall, the majority of computational evidence points to 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. | Likely Benign | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -4.204 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.03 | Neutral | 0.092 | Benign | 0.007 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1180 | 0.5003 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2311T>A | S771T 2D AIThe SynGAP1 missense variant S771T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and 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. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign impact. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. 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 | -4.765 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.38 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 4.07 | Benign | 0.23 | Tolerated | 0.1497 | 0.6310 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2311T>G | S771A 2D AIThe SynGAP1 missense variant S771A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—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 | -4.337 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.09 | Neutral | 0.025 | Benign | 0.014 | Benign | 4.09 | Benign | 0.62 | Tolerated | 0.5201 | 0.4745 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2314T>A | F772I 2D AIThe SynGAP1 missense variant F772I 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, 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 not available. Overall, the majority of evidence points to a benign impact. The predictions do 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.925 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -0.38 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.24 | Benign | 0.41 | Tolerated | 0.1544 | 0.2051 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>A | A774T 2D AIThe SynGAP1 missense variant A774T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.238 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.46 | Neutral | 0.037 | Benign | 0.063 | Benign | 4.20 | Benign | 0.39 | Tolerated | 0.1436 | 0.7578 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>C | A774P 2D AIThe SynGAP1 missense variant A774P 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 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 status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.869 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.94 | Neutral | 0.801 | Possibly Damaging | 0.481 | Possibly Damaging | 4.15 | Benign | 0.18 | Tolerated | 0.1902 | 0.5749 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>T | A774S 2D AIThe SynGAP1 missense variant A774S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -2.780 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.09 | Neutral | 0.071 | Benign | 0.115 | Benign | 4.27 | Benign | 0.43 | Tolerated | 0.2711 | 0.6399 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>G | A774G 2D AIThe SynGAP1 missense variant A774G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.129 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.68 | Neutral | 0.135 | Benign | 0.152 | Benign | 4.16 | Benign | 0.22 | Tolerated | 0.2392 | 0.5436 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2327G>C | G776A 2D AIThe SynGAP1 missense variant G776A 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 for G776A, 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 | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -5.275 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.82 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 4.26 | Benign | 0.03 | Affected | 0.3648 | 0.4971 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2333A>G | N778S 2D AIThe SynGAP1 missense variant N778S is reported in gnomAD (ID 6‑33442491‑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 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: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to 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 | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442491-A-G | 1 | 1.28e-6 | -2.711 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.61 | Neutral | 0.843 | Possibly Damaging | 0.893 | Possibly Damaging | 4.32 | Benign | 0.86 | Tolerated | 3.64 | 6 | 0.4285 | 0.6890 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||||
| c.2335A>G | S779G 2D AIThe SynGAP1 missense variant S779G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports 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 evidence strongly supports a benign classification, 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 | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.304 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.38 | Neutral | 0.393 | Benign | 0.324 | Benign | 2.65 | Benign | 0.53 | Tolerated | 0.2894 | 0.5087 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2336G>A | S779N 2D AIThe SynGAP1 missense variant S779N is listed in gnomAD (ID 6‑33442494‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign majority. The AlphaMissense‑Optimized score is benign, and no Foldetta stability assessment is available. Taken together, 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. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | 6-33442494-G-A | -4.880 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.75 | Neutral | 0.021 | Benign | 0.026 | Benign | 2.30 | Pathogenic | 0.23 | Tolerated | 3.64 | 6 | 0.1327 | 0.4984 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||
| c.2336G>C | S779T 2D AIThe SynGAP1 missense variant S779T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the consensus of available predictions points to a benign 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 Benign | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.458 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -0.71 | Neutral | 0.611 | Possibly Damaging | 0.396 | Benign | 2.34 | Pathogenic | 0.79 | Tolerated | 0.1491 | 0.6392 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2338T>A | S780T 2D AIThe SynGAP1 missense variant S780T is reported in ClinVar as “Not submitted” and is not present in 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. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. 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 majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -4.911 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.63 | Neutral | 0.951 | Possibly Damaging | 0.614 | Possibly Damaging | 2.66 | Benign | 0.84 | Tolerated | 0.1445 | 0.6631 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2338T>G | S780A 2D AIThe SynGAP1 missense variant S780A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” 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 preponderance of evidence indicates that S780A is most likely benign, 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 | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -5.627 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.40 | Neutral | 0.798 | Possibly Damaging | 0.340 | Benign | 2.69 | Benign | 0.74 | Tolerated | 0.4936 | 0.5522 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2341A>G | M781V 2D AIThe SynGAP1 missense variant M781V is catalogued in gnomAD (ID 6‑33442893‑A‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the evidence overwhelmingly supports a benign effect, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442893-A-G | 4 | 2.48e-6 | -2.624 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.174 | Likely Benign | 0.00 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.03 | Benign | 0.90 | Tolerated | 3.64 | 6 | 0.3081 | 0.2705 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.2343G>A | M781I 2D AIThe SynGAP1 missense variant M781I is listed in ClinVar (ID 2802065.0) as Benign and is not reported in gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 predictions strongly support a benign effect, consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | Benign | 1 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2343G>C | M781I 2D AIThe SynGAP1 missense variant M781I is catalogued in gnomAD (ID 6‑33442895‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the consensus of all available predictions is benign, 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442895-G-C | 1 | 6.21e-7 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.2343G>T | M781I 2D AIThe SynGAP1 missense variant M781I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the evidence strongly suggests that M781I is most likely benign, 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2344G>C | D782H 2D AIThe SynGAP1 missense variant D782H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only REVEL predicts a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show the SGM‑Consensus as Likely Pathogenic, whereas AlphaMissense‑Optimized remains inconclusive and Foldetta data are unavailable. Taken together, the majority of evidence supports a pathogenic interpretation, and this is consistent with the absence of a ClinVar assertion. Therefore, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -8.528 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 0.311 | Likely Benign | -2.63 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.1333 | 0.7286 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2345A>G | D782G 2D AIThe SynGAP1 missense variant D782G 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 ESM1b, whereas the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -6.811 | Likely Benign | 0.858 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.27 | Deleterious | 0.995 | Probably Damaging | 0.950 | Probably Damaging | 1.95 | Pathogenic | 0.02 | Affected | 0.3816 | 0.6318 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2347A>G | M783V 2D AIThe SynGAP1 missense variant M783V is catalogued in gnomAD (ID 6‑33442899‑A‑G) and has no ClinVar entry. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable. Consequently, the variant is most likely benign, and this prediction 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | 6-33442899-A-G | 1 | 6.21e-7 | -3.453 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.96 | Neutral | 0.072 | Benign | 0.026 | Benign | 2.85 | Benign | 0.12 | Tolerated | 3.64 | 6 | 0.3444 | 0.3710 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.2349G>A | M783I 2D AIThe SynGAP1 missense variant M783I is listed in ClinVar as a benign alteration (ClinVar ID 3618151.0) and is present in the gnomAD database (gnomAD ID 6‑33442901‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a likely benign effect. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly suggests that the variant is most likely benign, in agreement with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | Benign | 1 | 6-33442901-G-A | 6 | 3.72e-6 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2349G>C | M783I 2D AIThe SynGAP1 missense variant M783I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Consensus from multiple in‑silico predictors classifies the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all return benign scores, and AlphaMissense‑Optimized also predicts a benign effect. No tool in the set indicates pathogenicity. The high‑accuracy assessments corroborate this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and Foldetta data are unavailable. Consequently, the aggregate evidence strongly supports a benign interpretation for M783I, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2349G>T | M783I 2D AIThe SynGAP1 missense variant M783I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools uniformly indicate a benign effect. Benign calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. Foldetta stability analysis is unavailable, so it does not influence the assessment. Overall, the computational evidence strongly supports a benign classification for M783I, 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2350G>A | A784T 2D AIThe SynGAP1 missense variant A784T is listed in ClinVar (ID 962668.0) as Benign and is not reported in gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. A Foldetta stability analysis is unavailable, so it does not influence the overall interpretation. Based on the unanimous benign predictions and the ClinVar designation, the variant is most likely benign, with no contradiction to the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | Benign | 1 | -3.579 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 1.23 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1493 | 0.6659 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.2350G>T | A784S 2D AIThe SynGAP1 missense variant A784S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion 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. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | -2.233 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.41 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.72 | Benign | 0.67 | Tolerated | 0.2624 | 0.5171 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2359C>G | P787A 2D AIThe SynGAP1 P787A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM) predict a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic versus three benign predictions, with the SGM Consensus supporting pathogenicity—suggests that the variant is most likely pathogenic. 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. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -4.542 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -4.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 0.3425 | 0.4444 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2362T>A | S788T 2D AIThe SynGAP1 missense variant S788T is listed in ClinVar with an uncertain significance (ClinVar ID 392728.0) and is present in the gnomAD database (gnomAD ID 6‑33442914‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote) also favors a benign interpretation. No Foldetta stability prediction is available for this variant. Overall, the majority of computational 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 | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | Uncertain | 2 | 6-33442914-T-A | 4 | 2.49e-6 | -4.288 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -2.25 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 1.55 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.1794 | 0.6339 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||
| c.2362T>G | S788A 2D AIThe SynGAP1 missense variant S788A 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 outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for S788A. This consensus 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 | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | -5.381 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -2.24 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 1.59 | Pathogenic | 0.02 | Affected | 0.5079 | 0.5041 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||
| c.2365C>G | P789A 2D AIThe SynGAP1 P789A missense variant is not reported in ClinVar and is absent from gnomAD. 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 tie (2 benign, 2 pathogenic) and is therefore inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus remains inconclusive and Foldetta data are unavailable. Overall, the majority of tools (five out of nine) predict pathogenicity, but the presence of four benign predictions and the inconclusive high‑accuracy results suggest uncertainty. The variant is most likely pathogenic based on the current predictions, 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. | SH3-binding motif | 0.963420 | Disordered | 0.541575 | Binding | 0.398 | 0.903 | 0.750 | -4.777 | Likely Benign | 0.235 | Likely Benign | Likely Benign | 0.258 | Likely Benign | -4.92 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.11 | Pathogenic | 0.00 | Affected | 0.3120 | 0.3052 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2365C>T | P789S 2D AIThe SynGAP1 P789S variant has no ClinVar entry (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify it as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of 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 balance of evidence leans toward pathogenicity, with five tools supporting a deleterious effect versus three supporting benignity. This 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. | SH3-binding motif | 0.963420 | Disordered | 0.541575 | Binding | 0.398 | 0.903 | 0.750 | -4.793 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.221 | Likely Benign | -4.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.19 | Pathogenic | 0.00 | Affected | 0.3100 | 0.3436 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2368A>G | T790A 2D AIThe SynGAP1 T790A missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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, is inconclusive (2 benign vs. 2 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, while the SGM Consensus remains inconclusive and Foldetta data are unavailable. Overall, the majority of standard predictors indicate pathogenicity, but the single high‑accuracy tool that is available suggests a benign effect, and no high‑accuracy tool provides a definitive pathogenic verdict. Consequently, the variant is most likely pathogenic according to the bulk of predictions, 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. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | -4.337 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.64 | Deleterious | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.35 | Pathogenic | 0.02 | Affected | 0.4157 | 0.4207 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2368A>T | T790S 2D AIThe SynGAP1 missense variant T790S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for T790S, 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 | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | -3.914 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.39 | Pathogenic | 0.33 | Tolerated | 3.64 | 6 | 0.3416 | 0.4449 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.2369C>G | T790S 2D AIThe SynGAP1 missense variant T790S is listed in ClinVar (ID 1020340.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this 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 | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | Uncertain | 1 | -3.914 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.39 | Pathogenic | 0.33 | Tolerated | 3.64 | 6 | 0.3416 | 0.4449 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.236A>G | N79S 2D AIThe SynGAP1 missense variant N79S 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 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 | 0.618285 | Disordered | 0.457064 | Uncertain | 0.290 | 0.876 | 0.375 | -2.311 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.31 | Neutral | 0.113 | Benign | 0.011 | Benign | 4.29 | Benign | 0.00 | Affected | 0.3155 | 0.4740 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2371A>C | K791Q 2D AIThe SynGAP1 missense variant K791Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that K791Q 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 | 0.966441 | Disordered | 0.478670 | Uncertain | 0.356 | 0.896 | 0.875 | -3.418 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.09 | Neutral | 0.802 | Possibly Damaging | 0.335 | Benign | 4.17 | Benign | 0.46 | Tolerated | 0.5322 | 0.1159 | Weaken | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||
| c.2373G>C | K791N 2D AIThe SynGAP1 missense variant K791N 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of high‑accuracy predictions (SGM‑Consensus, AlphaMissense‑Optimized uncertain, Foldetta unavailable) lean toward a benign interpretation, with only two pathogenic calls. Thus, based on the current computational 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 | SH3-binding motif | 0.966441 | Disordered | 0.478670 | Uncertain | 0.356 | 0.896 | 0.875 | -4.001 | Likely Benign | 0.794 | Likely Pathogenic | Ambiguous | 0.027 | Likely Benign | -1.26 | Neutral | 0.666 | Possibly Damaging | 0.267 | Benign | 4.14 | Benign | 0.13 | Tolerated | 0.4578 | 0.1354 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.2373G>T | K791N 2D AIThe SynGAP1 missense variant K791N 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and 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 predictions (including the SGM‑Consensus) indicate a benign impact, and there is no conflict with ClinVar status. Thus, based on the current computational evidence, 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 | 0.966441 | Disordered | 0.478670 | Uncertain | 0.356 | 0.896 | 0.875 | -4.001 | Likely Benign | 0.794 | Likely Pathogenic | Ambiguous | 0.027 | Likely Benign | -1.26 | Neutral | 0.666 | Possibly Damaging | 0.267 | Benign | 4.14 | Benign | 0.13 | Tolerated | 0.4578 | 0.1354 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.2377A>C | K793Q 2D AIThe SynGAP1 missense variant K793Q is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are unavailable, so they do not influence the assessment. Overall, the variant is most likely benign, 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 | SH3-binding motif | 0.971072 | Disordered | 0.426071 | Uncertain | 0.344 | 0.901 | 0.875 | -2.838 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -0.83 | Neutral | 0.174 | Benign | 0.099 | Benign | 4.13 | Benign | 0.06 | Tolerated | 0.5276 | 0.1540 | Weaken | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||
| c.2377A>G | K793E 2D AIThe SynGAP1 missense variant K793E is listed in gnomAD (ID 6‑33442929‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. 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, 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 | SH3-binding motif | 0.971072 | Disordered | 0.426071 | Uncertain | 0.344 | 0.901 | 0.875 | 6-33442929-A-G | -4.233 | Likely Benign | 0.555 | Ambiguous | Likely Benign | 0.035 | Likely Benign | -1.05 | Neutral | 0.001 | Benign | 0.006 | Benign | 4.17 | Benign | 0.05 | Affected | 4.07 | 3 | 0.4670 | 0.1499 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.2380C>G | P794A 2D AIThe SynGAP1 missense variant P794A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable, so they do not influence the assessment. Overall, 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 | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -3.766 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.63 | Neutral | 0.124 | Benign | 0.089 | Benign | 4.27 | Benign | 0.09 | Tolerated | 0.3692 | 0.5209 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2380C>T | P794S 2D AIThe SynGAP1 missense variant P794S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -5.086 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.21 | Neutral | 0.025 | Benign | 0.010 | Benign | 4.29 | Benign | 0.13 | Tolerated | 0.3666 | 0.5604 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2383C>G | P795A 2D AIThe SynGAP1 missense variant P795A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. 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) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly suggests that P795A is most likely benign, 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 | SH3-binding motif | 0.972450 | Disordered | 0.410339 | Uncertain | 0.457 | 0.903 | 0.875 | -5.348 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.52 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.32 | Benign | 0.16 | Tolerated | 0.3672 | 0.5371 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2386C>T | P796S 2D AIThe SynGAP1 missense variant P796S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) reports likely benign. Foldetta results are not available for this variant. Based on the collective evidence, the variant is most likely benign, 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 | SH3-binding motif | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -5.382 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.05 | Neutral | 0.174 | Benign | 0.091 | Benign | 4.28 | Benign | 0.48 | Tolerated | 0.3560 | 0.4171 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2389C>G | P797A 2D AIThe SynGAP1 missense variant P797A 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. 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, so they do not influence the assessment. Overall, the majority of evidence indicates that P797A 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 | SH3-binding motif | 0.926919 | Disordered | 0.449970 | Uncertain | 0.561 | 0.902 | 0.875 | -5.548 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -0.33 | Neutral | 0.649 | Possibly Damaging | 0.535 | Possibly Damaging | 4.25 | Benign | 0.54 | Tolerated | 0.3704 | 0.4832 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2389C>T | P797S 2D AIThe SynGAP1 missense variant P797S 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 tolerated or benign, and 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. 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 P797S, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar. 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 | -6.232 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.14 | Neutral | 0.901 | Possibly Damaging | 0.637 | Possibly Damaging | 4.25 | Benign | 0.38 | Tolerated | 0.3634 | 0.5228 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.238A>C | K80Q 2D AIThe SynGAP1 missense variant K80Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT 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 also 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 | 0.637480 | Disordered | 0.477530 | Uncertain | 0.331 | 0.873 | 0.500 | -4.475 | Likely Benign | 0.662 | Likely Pathogenic | Likely Benign | 0.064 | Likely Benign | -0.81 | Neutral | 0.414 | Benign | 0.040 | Benign | 3.93 | Benign | 0.00 | Affected | 0.4373 | 0.1132 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2392C>G | P798A 2D AIThe SynGAP1 missense variant P798A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas only polyPhen‑2 HumDiv and SIFT predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the consensus of available predictions indicates that P798A 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 | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -4.841 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.57 | Neutral | 0.790 | Possibly Damaging | 0.353 | Benign | 4.27 | Benign | 0.00 | Affected | 0.3060 | 0.4030 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2392C>T | P798S 2D AIThe SynGAP1 missense variant P798S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign 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 Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.382 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.14 | Neutral | 0.818 | Possibly Damaging | 0.353 | Benign | 4.28 | Benign | 0.00 | Affected | 0.2950 | 0.4425 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2395C>G | P799A 2D AIThe SynGAP1 missense variant P799A 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) score; 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 analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for P799A, and this assessment is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. 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 | -4.660 | Likely Benign | 0.048 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.72 | Neutral | 0.798 | Possibly Damaging | 0.489 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 0.3488 | 0.4279 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2395C>T | P799S 2D AIThe SynGAP1 missense variant P799S 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 (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 P799S, 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 | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -4.635 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.73 | Neutral | 0.951 | Possibly Damaging | 0.593 | Possibly Damaging | 4.26 | Benign | 0.00 | Affected | 0.3411 | 0.4464 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2398G>A | G800S 2D AIThe SynGAP1 missense variant G800S is reported as “Likely Benign” by the SGM‑Consensus method and is absent from ClinVar and gnomAD. All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. 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 | -3.572 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.69 | Neutral | 0.292 | Benign | 0.157 | Benign | 2.78 | Benign | 0.60 | Tolerated | 0.2375 | 0.4923 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2402G>A | G801D 2D AIThe SynGAP1 missense variant G801D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta results are not available, so they do not influence the assessment. 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -5.312 | Likely Benign | 0.414 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -0.69 | Neutral | 0.611 | Possibly Damaging | 0.346 | Benign | 2.84 | Benign | 0.25 | Tolerated | 0.1631 | 0.1835 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.2402G>C | G801A 2D AIThe SynGAP1 missense variant G801A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. **Overall, the variant is most likely benign, 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -3.747 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.61 | Neutral | 0.025 | Benign | 0.034 | Benign | 2.83 | Benign | 0.50 | Tolerated | 0.3458 | 0.4681 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2405G>A | G802D 2D AIThe SynGAP1 missense variant G802D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33442957‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all classifying the change as benign. No tool predicts a pathogenic outcome. The high‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions 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 | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | Uncertain | 1 | 6-33442957-G-A | 1 | 6.20e-7 | -5.083 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -0.38 | Neutral | 0.126 | Benign | 0.138 | Benign | 2.72 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1993 | 0.2742 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||
| c.2405G>C | G802A 2D AIThe SynGAP1 missense variant G802A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G802A 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 | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -3.584 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.089 | Benign | 2.74 | Benign | 0.02 | Affected | 0.3779 | 0.4554 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| 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.2409A>C | K803N 2D AIThe SynGAP1 K803N 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, 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 rates the variant as 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, has no available result for this variant. Overall, more tools predict pathogenicity (five) than benignity (three), and the high‑accuracy assessments do not overturn this trend. 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. | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -5.039 | Likely Benign | 0.807 | Likely Pathogenic | Ambiguous | 0.045 | Likely Benign | -2.13 | Neutral | 0.896 | Possibly Damaging | 0.673 | Possibly Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.3805 | 0.2035 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2409A>T | K803N 2D AIThe SynGAP1 K803N 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, and ESM1b, whereas those that predict 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 because it yields a 2‑to‑2 split. 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 assessments do not overturn this trend. 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. | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -5.039 | Likely Benign | 0.807 | Likely Pathogenic | Ambiguous | 0.045 | Likely Benign | -2.13 | Neutral | 0.896 | Possibly Damaging | 0.673 | Possibly Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.3805 | 0.2035 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.240A>C | K80N 2D AIThe SynGAP1 K80N missense variant has no ClinVar record and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 predicting pathogenicity, whereas the SGM‑Consensus (majority vote) predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the overall distribution of predictions, the variant is most likely benign, 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 | 0.637480 | Disordered | 0.477530 | Uncertain | 0.331 | 0.873 | 0.500 | -5.072 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | -1.07 | Neutral | 0.588 | Possibly Damaging | 0.054 | Benign | 3.89 | Benign | 0.00 | Affected | 0.3749 | 0.1237 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.240A>T | K80N 2D AIThe SynGAP1 K80N missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote) remains benign; Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely benign, 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 | 0.637480 | Disordered | 0.477530 | Uncertain | 0.331 | 0.873 | 0.500 | -5.072 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.078 | Likely Benign | -1.07 | Neutral | 0.588 | Possibly Damaging | 0.054 | Benign | 3.89 | Benign | 0.00 | Affected | 0.3749 | 0.1237 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2410G>C | D804H 2D AIThe SynGAP1 D804H missense variant 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 outcome: 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 suggests that D804H 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 Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -5.100 | Likely Benign | 0.821 | Likely Pathogenic | Ambiguous | 0.296 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.975 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 0.1859 | 0.7607 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||
| c.2416T>A | F806I 2D AIThe SynGAP1 missense variant F806I 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, ESM1b, and AlphaMissense‑Optimized, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; Foldetta results are unavailable. Overall, the balance of evidence from the consensus of prediction algorithms points to a pathogenic impact for F806I. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -5.040 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | -3.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.15 | Pathogenic | 0.03 | Affected | 0.2583 | 0.1357 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2425A>G | S809G 2D AIThe SynGAP1 missense variant S809G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates 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 (majority vote) is also benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the preponderance of evidence indicates that S809G is most likely benign, 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 | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -6.100 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.80 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.61 | Benign | 0.02 | Affected | 0.2743 | 0.5369 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2426G>A | S809N 2D AIThe SynGAP1 missense variant S809N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact, while AlphaMissense‑Default remains uncertain. 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 this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for S809N, 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 | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -5.308 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.12 | Neutral | 0.784 | Possibly Damaging | 0.316 | Benign | 2.51 | Benign | 0.04 | Affected | 0.1363 | 0.5028 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.2426G>C | S809T 2D AIThe SynGAP1 missense variant S809T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -3.865 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.68 | Neutral | 0.003 | Benign | 0.010 | Benign | 2.95 | Benign | 0.82 | Tolerated | 0.1430 | 0.6617 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2431C>G | P811A 2D AIThe SynGAP1 missense variant P811A 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 supports a benign classification for P811A, 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 | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.120 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.11 | Neutral | 0.939 | Possibly Damaging | 0.670 | Possibly Damaging | 2.76 | Benign | 0.57 | Tolerated | 0.3763 | 0.5485 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| 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.2434C>G | P812A 2D AIThe SynGAP1 missense variant P812A 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 the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also 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 | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.113 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -1.49 | Neutral | 0.989 | Probably Damaging | 0.869 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 0.3555 | 0.5350 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2434C>T | P812S 2D AIThe SynGAP1 missense variant P812S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442986‑C‑T). 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, and no Foldetta stability result is available. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. 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 | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 1 | 6-33442986-C-T | 1 | 6.20e-7 | -5.689 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -0.62 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.89 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.3417 | 0.5699 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.2440G>A | A814T 2D AIThe SynGAP1 missense variant A814T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, while Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status. 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 | -3.600 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.24 | Neutral | 0.103 | Benign | 0.047 | Benign | 2.64 | Benign | 0.09 | Tolerated | 0.1400 | 0.6655 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| 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.2440G>T | A814S 2D AIThe SynGAP1 missense variant A814S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports 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 | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -2.542 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.22 | Neutral | 0.640 | Possibly Damaging | 0.386 | Benign | 2.63 | Benign | 0.06 | Tolerated | 0.2670 | 0.5366 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2441C>G | A814G 2D AIThe SynGAP1 missense variant A814G 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) score; 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. 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.659 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.83 | Neutral | 0.896 | Possibly Damaging | 0.649 | Possibly Damaging | 2.60 | Benign | 0.05 | Affected | 0.2336 | 0.4504 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| 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.2446T>C | S816P 2D AIThe SynGAP1 missense variant S816P 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 other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. 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 data are unavailable. Overall, the preponderance of evidence points to a benign effect for S816P, and this conclusion is not in 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 | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.662 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.26 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.66 | Benign | 0.45 | Tolerated | 0.2298 | 0.5102 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| 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.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>C | S817P 2D AIThe SynGAP1 missense variant S817P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, 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, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools and the consensus score indicate a pathogenic effect, 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 | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -4.633 | Likely Benign | 0.724 | Likely Pathogenic | Likely Benign | 0.201 | Likely Benign | -3.26 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | 0.2272 | 0.6023 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| 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.244C>G | L82V 2D AIThe SynGAP1 missense variant L82V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33425852‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments therefore indicate a benign likelihood: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is likely benign, and Foldetta data are missing. Overall, the majority of predictions support a benign impact, 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 | 0.637480 | Disordered | 0.517720 | Binding | 0.284 | 0.890 | 0.375 | 6-33425852-C-G | -6.701 | Likely Benign | 0.914 | Likely Pathogenic | Ambiguous | 0.065 | Likely Benign | -1.13 | Neutral | 0.371 | Benign | 0.024 | Benign | 3.72 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1467 | 0.2353 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.2452C>G | P818A 2D AIThe SynGAP1 missense variant P818A 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 opinion: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, and ESM1b, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default. When the predictions are grouped by consensus, four tools favor benign and four favor pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas 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 that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence from both consensus and high‑accuracy tools indicates that 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 | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -6.084 | Likely Benign | 0.820 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -4.37 | Deleterious | 0.543 | Possibly Damaging | 0.306 | Benign | 2.15 | Pathogenic | 0.06 | Tolerated | 0.3574 | 0.5724 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2455G>A | A819T 2D AIThe SynGAP1 missense variant A819T 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign) and Foldetta data are unavailable. 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 prevailing predictions, 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. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -3.421 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.287 | Likely Benign | -2.23 | Neutral | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 2.29 | Pathogenic | 0.01 | Affected | 0.1443 | 0.7583 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2455G>C | A819P 2D AIThe SynGAP1 missense variant A819P is not reported in ClinVar and has no entries in 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 and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. 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, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic impact for A819P, 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 | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.542 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.342 | Likely Benign | -3.18 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.17 | Pathogenic | 0.01 | Affected | 0.1920 | 0.5753 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2455G>T | A819S 2D AIThe SynGAP1 missense variant A819S 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for A819S, 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 | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -3.420 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -1.49 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.33 | Pathogenic | 0.27 | Tolerated | 0.2729 | 0.6404 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2456C>G | A819G 2D AIThe SynGAP1 missense variant A819G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs three pathogenic) support a benign classification. 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. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.730 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.116 | Likely Benign | -2.17 | Neutral | 0.104 | Benign | 0.121 | Benign | 2.29 | Pathogenic | 0.03 | Affected | 0.2363 | 0.5396 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2464A>G | T822A 2D AIThe SynGAP1 T822A missense variant has no ClinVar record and is not reported in gnomAD. 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus (majority vote) remains 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). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -3.695 | Likely Benign | 0.788 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.55 | Neutral | 0.987 | Probably Damaging | 0.891 | Possibly Damaging | 2.60 | Benign | 0.17 | Tolerated | 0.4566 | 0.4456 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2464A>T | T822S 2D AIThe SynGAP1 missense variant T822S 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 (Likely Benign). 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 results are not available. Overall, the majority of evidence points to a benign impact for T822S, 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 | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -1.710 | Likely Benign | 0.655 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -0.54 | Neutral | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 3.08 | Benign | 0.74 | Tolerated | 0.3794 | 0.4547 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2467A>G | S823G 2D AIThe SynGAP1 missense variant S823G 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 (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. 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 Uncertain, and the Foldetta stability analysis is unavailable. Based on the collective evidence, 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 | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.034 | Likely Benign | 0.822 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -2.59 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.96 | Pathogenic | 0.00 | Affected | 0.2855 | 0.5287 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2468G>A | S823N 2D AIThe SynGAP1 missense variant S823N 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. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, 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 available predictions, 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. | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.880 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -1.76 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.1370 | 0.5172 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2468G>C | S823T 2D AIThe SynGAP1 missense variant S823T 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. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized predicts benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.036 | Likely Benign | 0.717 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -2.02 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 0.1453 | 0.6580 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2471G>A | S824N 2D AIThe SynGAP1 missense variant S824N is reported in gnomAD (6‑33443023‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact 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, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, 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 | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | 6-33443023-G-A | 2 | 1.24e-6 | -4.473 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.08 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.61 | Tolerated | 3.77 | 5 | 0.1713 | 0.5327 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| c.2471G>C | S824T 2D AIThe SynGAP1 missense variant S824T 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 | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -4.135 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -0.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.62 | Benign | 0.47 | Tolerated | 0.1760 | 0.6525 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2473T>A | S825T 2D AIThe SynGAP1 missense variant S825T 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 high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized, a high‑accuracy model, 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 standard tools (5 pathogenic vs. 4 benign) suggest a pathogenic impact, while the single high‑accuracy model indicates benign. Thus, the variant is most likely pathogenic based on the collective predictions, 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. | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -4.659 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -2.26 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.07 | Pathogenic | 0.05 | Affected | 0.1432 | 0.6658 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2473T>C | S825P 2D AIThe SynGAP1 missense variant S825P 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 ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S825P 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 | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -3.227 | Likely Benign | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | -3.12 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 0.2060 | 0.5998 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2473T>G | S825A 2D AIThe SynGAP1 missense variant S825A is not reported in ClinVar (no entry) and is absent from gnomAD. Prediction tools that agree on benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on pathogenic are polyPhen‑2 (HumDiv and HumVar), SIFT, 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. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic effect, while the high‑accuracy AlphaMissense‑Optimized suggests benign and the consensus is neutral. Given the preponderance of pathogenic predictions and the lack of conflicting evidence from ClinVar or population databases, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -4.878 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.135 | Likely Benign | -2.30 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.04 | Pathogenic | 0.05 | Affected | 0.4794 | 0.5749 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.2476G>C | D826H 2D AIThe SynGAP1 missense variant D826H 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 ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: 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 D826H 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 | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.437 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.345 | Likely Benign | -3.00 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1757 | 0.8651 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2477A>G | D826G 2D AIThe SynGAP1 D826G 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction 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. | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.310 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.323 | Likely Benign | -2.94 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.4251 | 0.7480 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2479A>T | I827F 2D AIThe SynGAP1 missense variant I827F 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 change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also 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 give a benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data. Overall, the majority of evidence points to a benign effect, 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 Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -4.799 | Likely Benign | 0.517 | Ambiguous | Likely Benign | 0.155 | Likely Benign | -1.30 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.09 | Tolerated | 0.0490 | 0.2306 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2482A>T | T828S 2D AIThe SynGAP1 missense variant T828S 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 T828S 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 | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -2.851 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.49 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.52 | Tolerated | 0.3332 | 0.3913 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2488C>G | P830A 2D AIThe SynGAP1 missense variant P830A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. 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 predicts Benign, and the SGM‑Consensus likewise 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 the ClinVar status, which contains no entry for P830A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.618152 | Binding | 0.333 | 0.874 | 0.500 | -4.471 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.82 | Benign | 0.04 | Affected | 0.3534 | 0.5050 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2488C>T | P830S 2D AIThe SynGAP1 missense variant P830S 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, 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, 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 there is no ClinVar classification 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 | 0.590140 | Disordered | 0.618152 | Binding | 0.333 | 0.874 | 0.500 | -4.629 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.219 | Likely Benign | -3.23 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.28 | Tolerated | 0.3496 | 0.5450 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2494C>A | Q832K 2D AIThe SynGAP1 missense variant Q832K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. 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 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 | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -4.964 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.87 | Neutral | 0.811 | Possibly Damaging | 0.348 | Benign | 2.78 | Benign | 0.10 | Tolerated | 0.1759 | 0.3568 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2495A>G | Q832R 2D AIThe SynGAP1 missense variant Q832R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. 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 not available. Overall, the preponderance 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 | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -3.680 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.17 | Neutral | 0.912 | Possibly Damaging | 0.424 | Benign | 2.74 | Benign | 0.09 | Tolerated | 0.1494 | 0.1434 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
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