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.2872C>G | H958D 2D  AIThe SynGAP1 missense variant H958D 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and ESM1b—suggest a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and 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 | 0.985964 | Disordered | 0.976011 | Binding | 0.371 | 0.913 | 0.750 | -11.494 | Likely Pathogenic | 0.227 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -0.55 | Neutral | 0.925 | Possibly Damaging | 0.232 | Benign | 4.16 | Benign | 0.55 | Tolerated | 0.2732 | 0.2866 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.301C>G | H101D 2D AIThe SynGAP1 missense variant H101D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is not in conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.788 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.49 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.2479 | 0.2272 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3302C>G | P1101R 2D  AIThe SynGAP1 missense variant P1101R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.772 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.28 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 4.27 | Benign | 0.36 | Tolerated | 0.1497 | 0.4644 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.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.2803G>A | A935T 2D  AIThe SynGAP1 missense variant A935T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.980490 | Binding | 0.286 | 0.865 | 0.625 | -4.247 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -1.27 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1670 | 0.6599 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3194C>G | P1065R 2D AIThe SynGAP1 missense variant P1065R 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, 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 preponderance of evidence from multiple independent predictors indicates 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 | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -3.237 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.102 | Benign | 0.052 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 0.1439 | 0.4369 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>G | N1090S 2D  AIThe SynGAP1 missense variant N1090S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -2.451 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 2.97 | Benign | 0.38 | Tolerated | 0.3980 | 0.7620 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3410A>G | H1137R 2D  AIThe SynGAP1 missense variant H1137R is reported in gnomAD (ID 6‑33444445‑A‑G) but has no ClinVar entry. 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 AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | 6-33444445-A-G | 1 | 6.20e-7 | -3.468 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -1.19 | Neutral | 0.925 | Possibly Damaging | 0.629 | Possibly Damaging | 5.32 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2131 | 0.3449 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||
| c.3892C>A | Q1298K 2D  AIThe SynGAP1 missense variant Q1298K 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 is not contradicted by 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.415 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.27 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.86 | Benign | 0.24 | Tolerated | 0.1360 | 0.2903 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.115T>A | Y39N 2D  AIThe SynGAP1 missense variant Y39N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.098 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.84 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 0.2375 | 0.0903 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.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.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.2564T>G | L855R 2D  AIThe SynGAP1 missense variant L855R 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. 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 is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.485558 | Uncertain | 0.285 | 0.823 | 0.625 | -3.703 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.62 | Neutral | 0.026 | Benign | 0.015 | Benign | 4.00 | Benign | 0.03 | Affected | 0.1303 | 0.1187 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>C | S876P 2D  AIThe SynGAP1 missense variant S876P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions indicates that S876P 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 | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.002 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -2.04 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.56 | Benign | 0.35 | Tolerated | 0.1979 | 0.6928 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3082C>A | L1028M 2D  AIThe SynGAP1 missense variant L1028M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -4.591 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.07 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.70 | Benign | 0.18 | Tolerated | 0.0776 | 0.3124 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3212G>C | G1071A 2D  AIThe SynGAP1 missense variant G1071A 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. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 preponderance of evidence points to a benign effect, 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 | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -1.825 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.34 | Neutral | 0.025 | Benign | 0.022 | Benign | 4.12 | Benign | 0.05 | Affected | 0.3376 | 0.5084 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3239C>T | A1080V 2D  AIThe SynGAP1 missense variant A1080V is listed in gnomAD (ID 6‑33443791‑C‑T) 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 outcome 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; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | 6-33443791-C-T | -4.087 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.06 | Neutral | 0.481 | Possibly Damaging | 0.144 | Benign | 3.99 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1298 | 0.6056 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3308G>C | R1103P 2D  AIThe SynGAP1 missense variant R1103P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -2.149 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -2.48 | Neutral | 0.969 | Probably Damaging | 0.659 | Possibly Damaging | 2.43 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5109 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.343C>G | Q115E 2D  AIThe SynGAP1 missense variant Q115E is reported in gnomAD (variant ID 6‑33432208‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | 6-33432208-C-G | 1 | 6.20e-7 | -3.465 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.40 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.18 | Benign | 0.42 | Tolerated | 3.61 | 5 | 0.1377 | 0.1832 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.473A>T | Q158L 2D  AIThe SynGAP1 missense variant Q158L 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 from 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 Q158L, 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -5.965 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.652 | Possibly Damaging | 0.160 | Benign | 4.14 | Benign | 0.03 | Affected | 0.0711 | 0.4832 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.1090C>A | P364T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P364T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (FoldX, Foldetta, premPS, 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 evaluated tools (five benign versus four pathogenic) lean toward a benign classification, and this assessment 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. | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -7.951 | In-Between | 0.230 | Likely Benign | Likely Benign | 1.18 | Ambiguous | 0.6 | 0.47 | Likely Benign | 0.83 | Ambiguous | 0.53 | Ambiguous | 0.342 | Likely Benign | -5.60 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.60 | Pathogenic | 0.09 | Tolerated | 0.1660 | 0.5726 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1222A>C | T408P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX, premPS, and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable; Foldetta remains uncertain. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. 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 | -10.384 | Likely Pathogenic | 0.230 | Likely Benign | Likely Benign | 1.08 | Ambiguous | 0.3 | 2.27 | Destabilizing | 1.68 | Ambiguous | 0.73 | Ambiguous | 0.323 | Likely Benign | -4.19 | Deleterious | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 4.07 | Benign | 0.05 | Affected | 0.1985 | 0.5779 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.20C>A | S7Y 2D  AIThe SynGAP1 missense variant S7Y 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. 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 no ClinVar entry exists for this variant. 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 | -5.240 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -0.36 | Neutral | 0.561 | Possibly Damaging | 0.047 | Benign | 4.06 | Benign | 0.00 | Affected | 0.0708 | 0.5053 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2104C>G | Q702E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702E 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy methods further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign; Foldetta remains inconclusive. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -10.974 | Likely Pathogenic | 0.230 | Likely Benign | Likely Benign | 0.48 | Likely Benign | 0.0 | 0.72 | Ambiguous | 0.60 | Ambiguous | 0.27 | Likely Benign | 0.196 | Likely Benign | -2.27 | Neutral | 0.989 | Probably Damaging | 0.930 | Probably Damaging | 3.55 | Benign | 0.15 | Tolerated | 0.1021 | 0.1609 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.2725A>G | M909V 2D  AIThe SynGAP1 missense variant M909V is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. 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. 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 | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -2.906 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.88 | Neutral | 0.288 | Benign | 0.147 | Benign | 2.97 | Benign | 0.45 | Tolerated | 0.3295 | 0.3600 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.335G>T | G112V 2D  AIThe SynGAP1 missense variant G112V 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -2.411 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.159 | Likely Benign | -3.39 | Deleterious | 0.421 | Benign | 0.108 | Benign | 3.96 | Benign | 0.00 | Affected | 0.1225 | 0.4218 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3727C>A | Q1243K 2D AIThe SynGAP1 missense variant Q1243K is reported in gnomAD (6‑33446719‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | 6-33446719-C-A | 1 | 6.20e-7 | -7.110 | In-Between | 0.230 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -1.39 | Neutral | 0.679 | Possibly Damaging | 0.446 | Benign | 2.72 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.1276 | 0.2303 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||
| c.3749A>G | Q1250R 2D  AIThe SynGAP1 missense variant Q1250R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, 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 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 indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -5.183 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.76 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 3.09 | Benign | 1.00 | Tolerated | 0.1330 | 0.0874 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||
| c.183G>C | E61D 2D  AIThe SynGAP1 missense variant E61D 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, 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, 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. The variant’s predicted benign status does not contradict ClinVar, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -4.394 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.29 | Neutral | 0.267 | Benign | 0.585 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.1895 | 0.3851 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.183G>T | E61D 2D AIThe SynGAP1 missense variant E61D 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, 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, 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. The variant’s predicted benign status does not contradict ClinVar, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -4.394 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.29 | Neutral | 0.267 | Benign | 0.585 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.1895 | 0.3851 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1953G>C | E651D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E651D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen2_HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign prediction. 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -3.220 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.33 | Likely Benign | 0.25 | Likely Benign | -0.29 | Likely Benign | 0.153 | Likely Benign | -0.13 | Neutral | 0.906 | Possibly Damaging | 0.429 | Benign | 3.48 | Benign | 0.53 | Tolerated | 0.1813 | 0.3762 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1953G>T | E651D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E651D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only polyPhen2_HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign prediction. No prediction tool or stability analysis is inconclusive or missing. 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 | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -3.220 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.33 | Likely Benign | 0.25 | Likely Benign | -0.29 | Likely Benign | 0.153 | Likely Benign | -0.13 | Neutral | 0.906 | Possibly Damaging | 0.429 | Benign | 3.48 | Benign | 0.53 | Tolerated | 0.1813 | 0.3762 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2177G>A | R726K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726K 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, 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or folding‑stability result is missing or inconclusive. Based on the 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 | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -5.344 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | -0.02 | Likely Benign | 0.13 | Likely Benign | 0.20 | Likely Benign | 0.154 | Likely Benign | -0.63 | Neutral | 0.990 | Probably Damaging | 0.998 | Probably Damaging | 2.67 | Benign | 0.16 | Tolerated | 0.4920 | 0.4042 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||
| c.2560C>A | R854S 2D  AIThe SynGAP1 missense variant R854S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the preponderance of evidence points to a benign impact for R854S, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -1.42 | Neutral | 0.960 | Probably Damaging | 0.765 | Possibly Damaging | 4.14 | Benign | 0.26 | Tolerated | 0.3183 | 0.4687 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2642T>G | L881W 2D  AIThe SynGAP1 missense variant L881W 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -6.646 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.014 | Benign | 0.008 | Benign | 2.44 | Pathogenic | 0.00 | Affected | 0.0662 | 0.3288 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.3319C>G | Q1107E 2D AIThe SynGAP1 missense variant Q1107E 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.54 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.59 | Benign | 0.02 | Affected | 0.1453 | 0.2932 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.41C>A | P14H 2D  AIThe SynGAP1 missense variant P14H is listed in gnomAD (ID 6‑33420305‑C‑A) 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 outcome are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates 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 majority of predictions—including the high‑accuracy tools—indicate that P14H 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | 6-33420305-C-A | -3.747 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.27 | Neutral | 0.742 | Possibly Damaging | 0.091 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1999 | 0.5176 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| 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.3829C>T | H1277Y 2D  AIThe SynGAP1 missense variant H1277Y 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools 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 results are unavailable. Overall, the balance of evidence (5 benign vs 4 pathogenic predictions) leans toward a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -4.288 | Likely Benign | 0.232 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -4.32 | Deleterious | 0.812 | Possibly Damaging | 0.298 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.0742 | 0.3034 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||||||||
| 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.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.2867C>A | S956Y 2D AIThe SynGAP1 missense variant S956Y 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), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -4.920 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.90 | Neutral | 0.411 | Benign | 0.097 | Benign | 1.93 | Pathogenic | 0.22 | Tolerated | 0.1449 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.314C>T | S105L 2D  AIThe SynGAP1 missense variant S105L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432179‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy methods both support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | Uncertain | 2 | 6-33432179-C-T | 4 | 2.48e-6 | -3.710 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.52 | Neutral | 0.828 | Possibly Damaging | 0.048 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1161 | 0.5023 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.912C>A | D304E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.715 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.28 | Likely Benign | 0.48 | Likely Benign | 0.186 | Likely Benign | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.77 | Pathogenic | 0.04 | Affected | 0.1504 | 0.6998 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.912C>G | D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Overall, the balance of evidence favors a benign classification, 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. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.715 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.28 | Likely Benign | 0.48 | Likely Benign | 0.186 | Likely Benign | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.77 | Pathogenic | 0.04 | Affected | 0.1504 | 0.6998 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1247T>A | L416Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416Q 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only two tools, polyPhen‑2 (HumDiv and HumVar), predict a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the evidence strongly supports a benign classification for this variant, 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 | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -6.445 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 1.17 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.86 | Ambiguous | 0.88 | Ambiguous | 0.187 | Likely Benign | -1.07 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.46 | Tolerated | 0.1281 | 0.0860 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1750A>G | I584V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I584V is catalogued in gnomAD (ID 6‑33440802‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Two tools (FoldX and ESM1b) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic vote), and Foldetta predicts benign stability. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | 6-33440802-A-G | 1 | 6.20e-7 | -7.562 | In-Between | 0.234 | Likely Benign | Likely Benign | 0.67 | Ambiguous | 0.1 | 0.29 | Likely Benign | 0.48 | Likely Benign | 1.16 | Destabilizing | 0.405 | Likely Benign | -0.95 | Neutral | 0.642 | Possibly Damaging | 0.349 | Benign | -1.18 | Pathogenic | 0.18 | Tolerated | 3.37 | 34 | 0.1007 | 0.2659 | 3 | 4 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.2186A>T | N729I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729I is listed in gnomAD (ID 6‑33441651‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicting benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign impact. There is no ClinVar status to contradict this conclusion. 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 | 6-33441651-A-T | 1 | 6.20e-7 | -3.308 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.6 | 0.79 | Ambiguous | 0.67 | Ambiguous | 0.29 | Likely Benign | 0.043 | Likely Benign | -2.96 | Deleterious | 0.506 | Possibly Damaging | 0.243 | Benign | 3.26 | Benign | 0.13 | Tolerated | 3.59 | 7 | 0.0625 | 0.4698 | -3 | -2 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.2272T>A | Y758N 2D AIThe SynGAP1 missense variant Y758N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion 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 | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.316 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.32 | Neutral | 0.837 | Possibly Damaging | 0.631 | Possibly Damaging | 2.72 | Benign | 0.02 | Affected | 0.2467 | 0.0331 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2338T>C | S780P 2D AIThe SynGAP1 missense variant S780P is reported in gnomAD (ID 6‑33442890‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and 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 | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | 6-33442890-T-C | 1 | 6.22e-7 | -6.055 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.11 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.64 | Benign | 0.30 | Tolerated | 3.64 | 6 | 0.2086 | 0.6171 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.2573G>T | S858I 2D  AIThe SynGAP1 missense variant S858I 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 analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -6.973 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.53 | Neutral | 0.818 | Possibly Damaging | 0.932 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 0.1016 | 0.5680 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2588T>C | L863P 2D  AIThe SynGAP1 missense variant L863P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.594839 | Binding | 0.267 | 0.795 | 0.250 | -4.760 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -0.78 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 4.01 | Benign | 0.12 | Tolerated | 0.3520 | 0.1458 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2791C>G | L931V 2D  AIThe SynGAP1 missense variant L931V 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. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the L931V variant, and this conclusion does not contradict any ClinVar annotation, as none exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.989212 | Binding | 0.335 | 0.856 | 0.375 | -1.512 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.71 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.03 | Benign | 0.70 | Tolerated | 0.1690 | 0.3164 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3190C>A | Q1064K 2D AIThe SynGAP1 missense variant Q1064K 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 collective predictions strongly support a benign classification, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.953106 | Binding | 0.378 | 0.914 | 0.875 | -3.592 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.23 | Benign | 0.24 | Tolerated | 0.2758 | 0.4192 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.457A>G | T153A 2D  AIThe SynGAP1 missense variant T153A is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. 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, 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 points to a benign impact, 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 Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -3.016 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.54 | Neutral | 0.620 | Possibly Damaging | 0.220 | Benign | 4.15 | Benign | 0.05 | Affected | 0.4430 | 0.2985 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.1530T>G | I510M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I510M 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 impact include PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (benign), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign)—also favors benign. Foldetta, a protein‑folding stability method, yielded an uncertain outcome. Taken together, the consensus of the most reliable predictors indicates a benign effect. 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. | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -7.988 | In-Between | 0.235 | Likely Benign | Likely Benign | 0.56 | Ambiguous | 0.3 | 1.61 | Ambiguous | 1.09 | Ambiguous | 0.55 | Ambiguous | 0.532 | Likely Pathogenic | -0.97 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.42 | Pathogenic | 0.02 | Affected | 0.0674 | 0.1789 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.1585A>T | I529F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529F is not reported in ClinVar and is present in gnomAD (variant ID 6‑33438828‑A‑T). Consensus from most in‑silico predictors classifies the change as benign: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic effect. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized 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 preponderance of evidence indicates that I529F 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 | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | 6-33438828-A-T | 4 | 2.48e-6 | -5.669 | Likely Benign | 0.235 | Likely Benign | Likely Benign | -0.21 | Likely Benign | 0.0 | 0.06 | Likely Benign | -0.08 | Likely Benign | 0.06 | Likely Benign | 0.320 | Likely Benign | -0.97 | Neutral | 0.266 | Benign | 0.054 | Benign | -1.30 | Pathogenic | 0.23 | Tolerated | 3.37 | 35 | 0.0522 | 0.2713 | 0 | 1 | -1.7 | 34.02 | ||||||||||||||||||||||||
| 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.2875C>G | H959D 2D AIThe SynGAP1 missense variant H959D is listed in gnomAD (ID 6‑33443427‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none reported). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.980566 | Binding | 0.333 | 0.905 | 0.750 | 6-33443427-C-G | 1 | 6.20e-7 | -12.060 | Likely Pathogenic | 0.235 | Likely Benign | Likely Benign | 0.176 | Likely Benign | -0.73 | Neutral | 0.144 | Benign | 0.058 | Benign | 4.14 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.2586 | 0.3066 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.160A>C | N54H 2D  AISynGAP1 missense variant N54H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -7.646 | In-Between | 0.236 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.18 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.14 | Benign | 0.00 | Affected | 0.1377 | 0.7334 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.101A>C | Y34S 2D  AIThe SynGAP1 missense variant Y34S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Y34S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -0.994 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.60 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.19 | Benign | 0.00 | Affected | 0.4760 | 0.2884 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.1922C>T | S641L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. This conclusion 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. | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -9.501 | Likely Pathogenic | 0.237 | Likely Benign | Likely Benign | 0.33 | Likely Benign | 0.3 | -0.14 | Likely Benign | 0.10 | Likely Benign | 0.32 | Likely Benign | 0.103 | Likely Benign | -4.33 | Deleterious | 0.115 | Benign | 0.014 | Benign | 3.39 | Benign | 0.07 | Tolerated | 0.1248 | 0.5376 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||
| c.2009T>C | L670P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670P 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) predict a pathogenic impact. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are uncertain. 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 classification, and this is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -4.916 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.56 | Ambiguous | 0.3 | 1.83 | Ambiguous | 1.20 | Ambiguous | -0.25 | Likely Benign | 0.211 | Likely Benign | 2.42 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.41 | Benign | 0.26 | Tolerated | 0.3590 | 0.1474 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2623G>C | A875P 2D  AIThe SynGAP1 missense variant A875P 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). In contrast, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar all predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for A875P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -3.799 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.959 | Probably Damaging | 2.66 | Benign | 0.09 | Tolerated | 0.1750 | 0.5688 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2757G>C | Q919H 2D  AIThe SynGAP1 missense variant Q919H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, 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 | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.867 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -1.83 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.39 | Pathogenic | 0.03 | Affected | 0.1463 | 0.4203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2757G>T | Q919H 2D AIThe SynGAP1 missense variant Q919H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, 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 | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.867 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.83 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.39 | Pathogenic | 0.03 | Affected | 0.1463 | 0.4203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2869C>G | H957D 2D AIThe SynGAP1 missense variant H957D 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, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (7 benign vs 2 pathogenic) supports a benign classification. This prediction is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -8.777 | Likely Pathogenic | 0.237 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -0.77 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.45 | Pathogenic | 0.44 | Tolerated | 0.2646 | 0.3066 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2884C>G | H962D 2D AIThe SynGAP1 missense variant H962D 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only ESM1b 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. There is no ClinVar entry to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.991070 | Disordered | 0.984483 | Binding | 0.369 | 0.886 | 0.750 | -12.472 | Likely Pathogenic | 0.237 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -1.08 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.20 | Benign | 0.20 | Tolerated | 0.2402 | 0.2643 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3326T>A | L1109H 2D  AIThe SynGAP1 missense variant L1109H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of 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 | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -4.353 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -0.56 | Neutral | 0.832 | Possibly Damaging | 0.499 | Possibly Damaging | 2.70 | Benign | 0.04 | Affected | 0.1250 | 0.1845 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3579T>A | D1193E 2D AIThe SynGAP1 missense variant D1193E is predicted to be benign by the majority of in silico tools. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT classifies the change as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign effect: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. ClinVar contains no entry for this variant, and it is absent from gnomAD, so there is no external evidence to contradict the computational predictions. 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 | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -3.788 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -1.09 | Neutral | 0.008 | Benign | 0.028 | Benign | 5.47 | Benign | 0.00 | Affected | 0.1242 | 0.3957 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3579T>G | D1193E 2D AIThe SynGAP1 missense variant D1193E is not reported in ClinVar and is absent from gnomAD. 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 only pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence supports a benign classification for D1193E, 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 | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -3.788 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -1.09 | Neutral | 0.008 | Benign | 0.028 | Benign | 5.47 | Benign | 0.00 | Affected | 0.1242 | 0.3957 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3830A>T | H1277L 2D  AIThe SynGAP1 missense variant H1277L 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), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. 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 votes). 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 there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -2.949 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -7.93 | Deleterious | 0.224 | Benign | 0.091 | Benign | 2.17 | Pathogenic | 0.00 | Affected | 0.0822 | 0.4158 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.385T>C | S129P 2D AIThe SynGAP1 missense variant S129P 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, including the high‑accuracy predictors, 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 | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -2.469 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.09 | Neutral | 0.454 | Possibly Damaging | 0.133 | Benign | 4.11 | Benign | 0.32 | Tolerated | 0.1998 | 0.4989 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3877G>A | D1293N 2D  AIThe SynGAP1 missense variant D1293N is reported in gnomAD (6‑33447925‑G‑A) but has no ClinVar entry. Functional prediction tools split in a 5‑to‑4 ratio: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. 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. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | 6-33447925-G-A | 5 | 3.22e-6 | -3.983 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -3.30 | Deleterious | 0.950 | Possibly Damaging | 0.414 | Benign | 2.33 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1264 | 0.3421 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.38T>A | I13N 2D  AIThe SynGAP1 missense variant I13N is reported in gnomAD (ID 6‑33420302‑T‑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 it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.482657 | Uncertain | 0.318 | 0.916 | 0.375 | 6-33420302-T-A | -3.725 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.16 | Neutral | 0.056 | Benign | 0.005 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1220 | 0.1100 | -3 | -2 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.1048G>C | V350L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L 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, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support, 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 | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | 0.042 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 0.1173 | 0.4958 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1048G>T | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L 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, Rosetta, 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other tools provide conflicting evidence. Based on the preponderance of predictions, V350L 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 | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | 0.042 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 0.1173 | 0.4958 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1082A>T | Q361L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q361L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. 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 (8 benign vs 5 pathogenic) favor a benign effect, and this consensus does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -10.678 | Likely Pathogenic | 0.238 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.29 | Likely Benign | 0.21 | Likely Benign | 0.406 | Likely Benign | -3.95 | Deleterious | 0.987 | Probably Damaging | 0.953 | Probably Damaging | 1.71 | Pathogenic | 0.06 | Tolerated | 0.0720 | 0.5213 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| 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.373C>T | P125S 2D  AIThe SynGAP1 missense variant P125S is listed in ClinVar (ID 837156.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | Uncertain | 1 | -3.769 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -3.57 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.86 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3408 | 0.4594 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3875T>G | L1292R 2D AIThe SynGAP1 missense variant L1292R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -4.249 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -4.34 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.1286 | 0.0849 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.866T>C | M289T 2D  AIThe SynGAP1 missense variant M289T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. 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, is labeled likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a benign effect. Taken together, the majority of evidence indicates that M289T is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | Uncertain | 1 | -4.668 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.17 | Likely Benign | 0.45 | Likely Benign | -0.01 | Likely Benign | 0.222 | Likely Benign | -0.47 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 1.83 | Pathogenic | 0.57 | Tolerated | 0.1657 | 0.1534 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||
| 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.23T>C | I8T 2D  AIThe SynGAP1 missense variant I8T is reported in gnomAD (variant ID 6‑33420287‑T‑C) 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, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. 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 | 6-33420287-T-C | -3.149 | Likely Benign | 0.239 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -0.10 | Neutral | 0.047 | Benign | 0.006 | Benign | 4.03 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0949 | 0.1019 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||
| c.2846G>A | G949D 2D  AIThe SynGAP1 missense variant G949D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (5 pathogenic vs. 4 benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -8.692 | Likely Pathogenic | 0.239 | Likely Benign | Likely Benign | 0.316 | Likely Benign | 0.25 | Neutral | 0.945 | Possibly Damaging | 0.753 | Possibly Damaging | 2.21 | Pathogenic | 0.02 | Affected | 0.1927 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.677C>T | S226L 2D AIThe SynGAP1 missense variant S226L 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 FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -6.098 | Likely Benign | 0.239 | Likely Benign | Likely Benign | -0.12 | Likely Benign | 0.5 | -0.14 | Likely Benign | -0.13 | Likely Benign | 0.36 | Likely Benign | 0.578 | Likely Pathogenic | -3.87 | Deleterious | 0.437 | Benign | 0.048 | Benign | 5.73 | Benign | 0.03 | Affected | 0.1525 | 0.5907 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.172A>C | M58L 2D  AIThe SynGAP1 missense variant M58L 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 substitution as tolerated or benign. Only SIFT predicts a deleterious impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus result is benign; Foldetta data are not available. Consequently, the aggregate evidence points to a benign effect for M58L, 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 | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -0.661 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.11 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.77 | Benign | 0.00 | Affected | 0.1514 | 0.4621 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.172A>T | M58L 2D AIThe SynGAP1 missense variant M58L 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 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 | 0.188120 | Structured | 0.484415 | Uncertain | 0.515 | 0.665 | 0.000 | -0.661 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.11 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.77 | Benign | 0.00 | Affected | 0.1514 | 0.4621 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2195G>A | R732K 2D AIThe SynGAP1 missense variant R732K is listed in ClinVar (ID 537019.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33441660‑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 (Likely Benign). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this consensus does not conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | Conflicting | 2 | 6-33441660-G-A | 4 | 2.48e-6 | -5.278 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.82 | Neutral | 0.973 | Probably Damaging | 0.943 | Probably Damaging | 2.69 | Benign | 0.21 | Tolerated | 3.59 | 7 | 0.4194 | 0.3923 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||
| c.2265G>A | M755I 2D  AIThe SynGAP1 missense variant M755I 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 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>C | M755I 2D AIThe SynGAP1 missense variant M755I 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 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>T | M755I 2D AIThe SynGAP1 missense variant M755I 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 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2530C>G | L844V 2D AIThe SynGAP1 missense variant L844V 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 | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | 0.094 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.043 | Likely Benign | 0.20 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.87 | Benign | 0.62 | Tolerated | 0.1692 | 0.3744 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3977C>G | P1326R 2D AIThe SynGAP1 missense variant P1326R is listed in ClinVar (ID 2429486.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. 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 | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | Uncertain | 1 | -5.097 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.82 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1710 | 0.2808 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.706G>A | A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -8.319 | Likely Pathogenic | 0.240 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.16 | Ambiguous | 0.83 | Ambiguous | 0.811 | Likely Pathogenic | -3.35 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 0.1342 | 0.6926 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1851G>C | E617D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E617D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, premPS, 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 further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. Based on the preponderance of evidence from both general and high‑accuracy predictors, 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | 0.322 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 0.1854 | 0.3386 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.1851G>T | E617D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617D is listed in ClinVar with an uncertain significance (ID 2584916.0) and is not reported in 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 score all indicate benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact, while Rosetta remains inconclusive. 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; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence supports a benign classification, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | Uncertain | 1 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | 0.322 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 0.1854 | 0.3386 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.217A>G | R73G 2D  AIThe SynGAP1 missense variant R73G 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 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 | 0.501700 | Disordered | 0.453164 | Uncertain | 0.332 | 0.826 | 0.375 | -3.556 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -1.48 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.03 | Benign | 0.00 | Affected | 0.3465 | 0.3608 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3103C>G | P1035A 2D AIThe SynGAP1 missense variant P1035A 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 outcome, creating a single discordant signal. 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 predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -4.293 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.02 | Neutral | 0.481 | Possibly Damaging | 0.222 | Benign | 2.74 | Benign | 0.41 | Tolerated | 0.3188 | 0.6022 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.86T>G | M29R 2D  AIThe SynGAP1 missense variant M29R 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this 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 | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -1.708 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.92 | Neutral | 0.042 | Benign | 0.184 | Benign | 4.23 | Benign | 0.00 | Affected | 0.2076 | 0.1293 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.1524T>A | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D508E is reported in gnomAD (ID 6‑33438556‑T‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑stability method Foldetta. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments further support a benign interpretation: 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) also indicates benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | 6-33438556-T-A | 1 | 6.20e-7 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||
| c.1524T>G | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as benign. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. 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 | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.3005A>C | H1002P 2D  AIThe SynGAP1 missense variant H1002P 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, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the majority of predictions and the high‑accuracy consensus, 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -4.616 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -2.02 | Neutral | 0.989 | Probably Damaging | 0.874 | Possibly Damaging | 2.77 | Benign | 0.28 | Tolerated | 0.2015 | 0.3738 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3131C>G | P1044R 2D AIThe SynGAP1 missense variant P1044R 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 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 | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -3.969 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.368 | Likely Benign | 0.79 | Neutral | 0.259 | Benign | 0.140 | Benign | 5.45 | Benign | 1.00 | Tolerated | 0.1451 | 0.4270 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3980C>T | P1327L 2D  AIThe SynGAP1 missense variant P1327L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33451854‑C‑T). 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 high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a benign outcome. Foldetta results are not available for this variant. Overall, the majority of computational evidence 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 | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451854-C-T | 2 | 1.28e-6 | -5.264 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.24 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.12 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.2123 | 0.5538 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.2412C>A | D804E 2D AIThe SynGAP1 D804E missense variant 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. 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 | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.155 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -2.03 | Neutral | 0.400 | Benign | 0.138 | Benign | 1.26 | Pathogenic | 0.04 | Affected | 0.1765 | 0.6850 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2412C>G | D804E 2D AIThe SynGAP1 D804E missense variant 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. 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 | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.155 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -2.03 | Neutral | 0.400 | Benign | 0.138 | Benign | 1.26 | Pathogenic | 0.04 | Affected | 0.1765 | 0.6850 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2612A>G | H871R 2D AIThe SynGAP1 missense variant H871R 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 | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.894 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.90 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.67 | Benign | 0.23 | Tolerated | 0.1632 | 0.2099 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.2840G>A | G947E 2D  AIThe SynGAP1 missense variant G947E is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33443392-G-A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G947E 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 | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | 6-33443392-G-A | 1 | 6.20e-7 | -9.574 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.302 | Likely Benign | 0.08 | Neutral | 0.126 | Benign | 0.096 | Benign | 4.92 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.1555 | 0.4259 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.2878C>G | H960D 2D AIThe SynGAP1 missense variant H960D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The predictions do 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 | 0.987911 | Disordered | 0.983385 | Binding | 0.380 | 0.901 | 0.750 | -12.235 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -1.09 | Neutral | 0.494 | Possibly Damaging | 0.170 | Benign | 4.19 | Benign | 0.31 | Tolerated | 0.2504 | 0.2923 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3872T>C | L1291P 2D AIThe SynGAP1 missense variant L1291P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. Because there is no ClinVar assertion, this prediction does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -3.322 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.417 | Likely Benign | -4.32 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.3078 | 0.2162 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.770G>C | S257T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict 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 reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority benign) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that S257T 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 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -8.603 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.42 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.13 | Likely Benign | 0.06 | Likely Benign | 0.472 | Likely Benign | -1.58 | Neutral | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.83 | Benign | 0.48 | Tolerated | 0.1073 | 0.4898 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.29G>T | R10L 2D  AIThe SynGAP1 missense variant R10L 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.513657 | Binding | 0.330 | 0.915 | 0.625 | -3.269 | Likely Benign | 0.244 | Likely Benign | Likely Benign | 0.143 | Likely Benign | 0.09 | Neutral | 0.058 | Benign | 0.009 | Benign | 4.21 | Benign | 0.00 | Affected | 0.2255 | 0.5261 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3070C>G | L1024V 2D AIThe SynGAP1 missense variant L1024V 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 the variant. 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 | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.758 | Likely Benign | 0.244 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.33 | Neutral | 0.907 | Possibly Damaging | 0.642 | Possibly Damaging | 2.47 | Pathogenic | 0.08 | Tolerated | 0.1459 | 0.3185 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.460A>T | S154C 2D  AIThe SynGAP1 missense variant S154C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and Foldetta results are unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. With the majority of evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -7.728 | In-Between | 0.244 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.841 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 0.1288 | 0.5042 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.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.1540A>G | I514V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514V is catalogued in gnomAD (variant ID 6‑33438783‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are limited to polyPhen‑2 HumDiv and HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence indicates that I514V 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 | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | 6-33438783-A-G | 7 | 4.34e-6 | -5.187 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 1.39 | Ambiguous | 0.0 | 0.44 | Likely Benign | 0.92 | Ambiguous | 0.89 | Ambiguous | 0.173 | Likely Benign | -0.79 | Neutral | 0.914 | Possibly Damaging | 0.960 | Probably Damaging | 3.15 | Benign | 0.13 | Tolerated | 3.37 | 35 | 0.0939 | 0.2130 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||
| c.2243T>G | L748R 2D AIThe SynGAP1 missense variant L748R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441708‑T‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.611637 | Binding | 0.339 | 0.863 | 0.750 | Conflicting | 2 | 6-33441708-T-G | 3 | 1.86e-6 | -3.331 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.67 | Neutral | 0.912 | Possibly Damaging | 0.448 | Possibly Damaging | 2.73 | Benign | 0.02 | Affected | 4.32 | 2 | 0.1342 | 0.0888 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||
| c.2686G>T | G896C 2D  AIThe SynGAP1 missense variant G896C 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, 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. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -5.607 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -2.59 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.50 | Benign | 0.10 | Tolerated | 0.1270 | 0.4369 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2849G>A | G950D 2D AIThe SynGAP1 missense variant G950D 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), AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -7.515 | In-Between | 0.245 | Likely Benign | Likely Benign | 0.402 | Likely Benign | -0.61 | Neutral | 0.411 | Benign | 0.131 | Benign | 2.26 | Pathogenic | 0.02 | Affected | 0.1874 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| 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.3307C>T | R1103C 2D  AISynGAP1 missense variant R1103C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443859‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized reports a benign outcome, while Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443859-C-T | 6 | 3.92e-6 | -2.440 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -3.01 | Deleterious | 0.996 | Probably Damaging | 0.787 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3376 | 0.4121 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.3391C>T | P1131S 2D AIThe SynGAP1 missense variant P1131S is reported in gnomAD (variant ID 6‑33443943‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. In contrast, PROVEAN 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | 6-33443943-C-T | 1 | 6.72e-7 | -4.089 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -2.62 | Deleterious | 0.025 | Benign | 0.015 | Benign | 5.54 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2936 | 0.5936 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3704T>G | M1235R 2D AIThe SynGAP1 missense variant M1235R 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. Only SIFT 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 results are not available. Overall, the preponderance of evidence indicates 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 | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -5.410 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.37 | Neutral | 0.270 | Benign | 0.089 | Benign | 2.64 | Benign | 0.00 | Affected | 0.1505 | 0.0757 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||
| c.1022G>T | G341V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, polyPhen‑2 HumVar, and the SGM‑Consensus score (derived from a majority of benign calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No evidence from FoldX or premPS is available. Overall, the majority of predictions support a benign classification, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign and does not contradict any existing ClinVar status. 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 | -5.371 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.3 | -2.24 | Stabilizing | -0.69 | Ambiguous | -0.50 | Ambiguous | 0.459 | Likely Benign | -2.29 | Neutral | 0.801 | Possibly Damaging | 0.192 | Benign | 0.42 | Pathogenic | 0.05 | Affected | 0.1019 | 0.3649 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| 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.1601C>G | S534C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534C 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 is uncertain, so both are treated as unavailable. No other high‑accuracy predictions are available. Overall, the evidence is evenly split between benign and pathogenic predictions, leaving the variant’s clinical significance inconclusive. There is no ClinVar status to contradict this balanced prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -8.077 | Likely Pathogenic | 0.247 | Likely Benign | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.56 | Ambiguous | 0.308 | Likely Benign | -4.05 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0984 | 0.4861 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.2549G>A | G850E 2D AIThe SynGAP1 missense variant G850E 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 classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, 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 majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation. The variant is most likely benign based on predictions, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -4.052 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -0.60 | Neutral | 0.770 | Possibly Damaging | 0.327 | Benign | 4.28 | Benign | 0.02 | Affected | 0.1612 | 0.4232 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3694A>C | K1232Q 2D AIThe SynGAP1 missense variant K1232Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of individual predictors (five pathogenic vs four benign) lean toward a pathogenic interpretation. 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 change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.505461 | Disordered | 0.542907 | Binding | 0.894 | 0.535 | 0.125 | -6.905 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.3457 | 0.1419 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3946A>C | N1316H 2D AIThe SynGAP1 missense variant N1316H is reported in gnomAD (ID 6‑33451820‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned to the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451820-A-C | -4.151 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.87 | Neutral | 0.939 | Possibly Damaging | 0.496 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1535 | 0.6636 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||
| c.886T>G | S296A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296A (ClinVar ID 469166.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or neutral. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign effect. No evidence from the available tools suggests a deleterious impact. Therefore, the variant is most likely benign, and this conclusion is consistent with its ClinVar status of Uncertain rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | Uncertain | 1 | -6.847 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.3 | -0.26 | Likely Benign | 0.12 | Likely Benign | 0.35 | Likely Benign | 0.209 | Likely Benign | -1.79 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.97 | Pathogenic | 0.65 | Tolerated | 3.40 | 16 | 0.4958 | 0.5522 | 1 | 1 | 2.6 | -16.00 | 182.5 | 26.6 | -0.2 | 0.1 | -0.5 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations. | ||||||||||||||||
| c.1276A>C | N426H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426H 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX and ESM1b. 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 tool is missing or inconclusive in this set. 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. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -7.004 | In-Between | 0.248 | Likely Benign | Likely Benign | 0.64 | Ambiguous | 0.0 | -0.14 | Likely Benign | 0.25 | Likely Benign | 0.24 | Likely Benign | 0.237 | Likely Benign | -3.57 | Deleterious | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 3.29 | Benign | 0.14 | Tolerated | 0.1267 | 0.3124 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.1853A>C | Q618P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM Consensus, ESM1b, FATHMM, PROVEAN, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. Overall, the majority of predictions lean toward a benign effect, though a subset of high‑confidence tools suggest pathogenicity. The variant’s status is not contradicted by ClinVar, which has no entry for this change. Based on the collective evidence, Q618P is most likely benign, albeit with some conflicting pathogenic signals from high‑accuracy predictors. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -8.273 | Likely Pathogenic | 0.248 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.1 | 3.41 | Destabilizing | 1.65 | Ambiguous | 0.23 | Likely Benign | 0.449 | Likely Benign | -3.32 | Deleterious | 0.261 | Benign | 0.246 | Benign | -1.35 | Pathogenic | 0.08 | Tolerated | 0.1990 | 0.4011 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.2315T>G | F772C 2D  AIThe SynGAP1 missense variant F772C 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 any ClinVar status, as no ClinVar claim 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 | -4.498 | Likely Benign | 0.248 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -1.46 | Neutral | 0.979 | Probably Damaging | 0.985 | Probably Damaging | 4.14 | Benign | 0.10 | Tolerated | 0.2450 | 0.1419 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.2542G>T | G848C 2D AIThe SynGAP1 missense variant G848C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -6.987 | Likely Benign | 0.248 | Likely Benign | Likely Benign | 0.237 | Likely Benign | -1.14 | Neutral | 0.998 | Probably Damaging | 0.922 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 0.1264 | 0.4400 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.1010A>G | K337R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K337R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign and pathogenic groups: benign predictions come from REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from polyPhen2_HumDiv, polyPhen2_HumVar, and FATHMM, while Rosetta remains uncertain. High‑accuracy methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Consequently, 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 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -6.302 | Likely Benign | 0.249 | Likely Benign | Likely Benign | -0.30 | Likely Benign | 0.2 | 1.07 | Ambiguous | 0.39 | Likely Benign | 0.12 | Likely Benign | 0.142 | Likely Benign | -2.36 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.70 | Pathogenic | 0.07 | Tolerated | 0.3913 | 0.1134 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.2479A>G | I827V 2D AIThe SynGAP1 missense variant I827V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the I827V 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 | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -3.590 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.129 | Likely Benign | 0.05 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.70 | Benign | 1.00 | Tolerated | 0.1011 | 0.2536 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2732T>C | V911A 2D  AIThe SynGAP1 missense variant V911A is not reported in ClinVar and is absent from gnomAD. 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. Based on the consensus of all 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 | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -3.030 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.08 | Neutral | 0.264 | Benign | 0.102 | Benign | 2.77 | Benign | 0.41 | Tolerated | 0.3069 | 0.3336 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.287G>A | G96D 2D AIThe SynGAP1 missense variant G96D 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, 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 | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | -3.699 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.95 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.18 | Benign | 0.00 | Affected | 0.2283 | 0.3150 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3621G>C | E1207D 2D AIThe SynGAP1 missense variant E1207D 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all classify the change as tolerated or benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy tools that were available give a benign verdict: AlphaMissense‑Optimized is benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. Foldetta results are not reported, so they do not influence the assessment. Overall, the majority of evidence supports a benign interpretation, and this is consistent with the lack of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -3.924 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.010 | Likely Benign | -1.16 | Neutral | 0.121 | Benign | 0.069 | Benign | 2.26 | Pathogenic | 0.51 | Tolerated | 0.1485 | 0.2810 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3621G>T | E1207D 2D AIThe SynGAP1 missense variant E1207D 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only FATHMM predicts it as pathogenic. 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 also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that 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 | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -3.924 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.010 | Likely Benign | -1.16 | Neutral | 0.121 | Benign | 0.069 | Benign | 2.26 | Pathogenic | 0.51 | Tolerated | 0.1485 | 0.2810 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.46A>C | M16L 2D AIThe SynGAP1 missense variant M16L 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. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -1.277 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.37 | Benign | 0.00 | Affected | 0.1805 | 0.4629 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.46A>T | M16L 2D AIThe SynGAP1 missense variant M16L 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 | 0.440853 | Structured | 0.459925 | Uncertain | 0.346 | 0.908 | 0.375 | -1.277 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.37 | Benign | 0.00 | Affected | 0.1805 | 0.4629 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.507C>A | D169E 2D AIThe SynGAP1 missense variant D169E 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 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 | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 0.1636 | 0.7316 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.507C>G | D169E 2D AIThe SynGAP1 missense variant D169E 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 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 | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 0.1636 | 0.7316 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1673A>T | H558L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H558L missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, ESM1b, and FATHMM; FoldX 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 as benign. With eight benign versus five pathogenic predictions and two high‑accuracy benign calls, the variant is most likely benign. This conclusion is not contradicted by ClinVar, which contains no entry for H558L. 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 | -13.563 | Likely Pathogenic | 0.250 | Likely Benign | Likely Benign | -0.52 | Ambiguous | 0.0 | 0.21 | Likely Benign | -0.16 | Likely Benign | 0.30 | Likely Benign | 0.509 | Likely Pathogenic | -5.40 | Deleterious | 0.001 | Benign | 0.005 | Benign | -0.98 | Pathogenic | 0.29 | Tolerated | 0.1002 | 0.3141 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.20C>T | S7F 2D  AIThe SynGAP1 missense variant S7F 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available 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 | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -4.346 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.24 | Neutral | 0.296 | Benign | 0.032 | Benign | 4.06 | Benign | 0.00 | Affected | 0.0622 | 0.5177 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.233G>A | R78H 2D  AIThe SynGAP1 R78H missense variant has no ClinVar entry and is not reported in gnomAD. 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, 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 majority of evidence points to a benign effect, and this conclusion 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 | 0.505461 | Disordered | 0.448183 | Uncertain | 0.304 | 0.866 | 0.500 | -4.851 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.38 | Neutral | 0.908 | Possibly Damaging | 0.108 | Benign | 3.83 | Benign | 0.00 | Affected | 0.2453 | 0.1601 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||||||||
| c.235A>T | N79Y 2D  AIThe SynGAP1 missense variant N79Y 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). 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 | -2.844 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -1.35 | Neutral | 0.939 | Possibly Damaging | 0.114 | Benign | 4.13 | Benign | 0.00 | Affected | 0.0510 | 0.4389 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>A | S1108N 2D  AIThe SynGAP1 missense variant S1108N 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1108N, 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 | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.488 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -2.02 | Neutral | 0.611 | Possibly Damaging | 0.239 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 0.1283 | 0.3952 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3866A>C | K1289T 2D  AIThe SynGAP1 missense variant K1289T is not reported in ClinVar and is absent from gnomAD. Consensus prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this residue. 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.618 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.18 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.58 | Benign | 0.02 | Affected | 0.2047 | 0.2447 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.205A>T | I69F 2D AIThe SynGAP1 missense variant I69F is reported in gnomAD (variant ID 6‑33425813‑A‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is also benign. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that I69F is most likely benign, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.466129 | Uncertain | 0.437 | 0.786 | 0.375 | 6-33425813-A-T | 2 | 1.24e-6 | -3.747 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.99 | Neutral | 0.824 | Possibly Damaging | 0.507 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0412 | 0.2743 | 0 | 1 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||
| 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.3840G>A | M1280I 2D AIThe SynGAP1 missense variant M1280I 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), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points 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. | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -3.723 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -2.59 | Deleterious | 0.059 | Benign | 0.041 | Benign | 2.35 | Pathogenic | 0.00 | Affected | 0.0995 | 0.2468 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3840G>C | M1280I 2D AIThe SynGAP1 missense variant M1280I 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), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points 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. | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -3.723 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -2.59 | Deleterious | 0.059 | Benign | 0.041 | Benign | 2.35 | Pathogenic | 0.00 | Affected | 0.0995 | 0.2468 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3840G>T | M1280I 2D AIThe SynGAP1 missense variant M1280I 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), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points 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. | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -3.723 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -2.59 | Deleterious | 0.059 | Benign | 0.041 | Benign | 2.35 | Pathogenic | 0.00 | Affected | 0.0995 | 0.2468 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.388C>G | Q130E 2D AIThe SynGAP1 missense variant Q130E is reported in gnomAD (ID 6‑33432685‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | 6-33432685-C-G | 2 | 1.24e-6 | -4.283 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.72 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.1620 | 0.2587 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.53A>G | Y18C 2D  AIThe SynGAP1 missense variant Y18C is listed in ClinVar (ID 1967233) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33420317‑A‑G). 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 high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, and AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | Uncertain | 2 | 6-33420317-A-G | 44 | 2.88e-5 | -2.658 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.56 | Neutral | 0.872 | Possibly Damaging | 0.206 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3293 | 0.2473 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||
| c.1502T>C | I501T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501T 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and premPS, while Rosetta remains uncertain. 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward 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. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | Uncertain | 1 | -5.996 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 2.40 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.11 | Destabilizing | 1.57 | Destabilizing | 0.362 | Likely Benign | -3.48 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.44 | Benign | 0.16 | Tolerated | 3.37 | 35 | 0.0972 | 0.0640 | 0 | -1 | -5.2 | -12.05 | 214.5 | 26.9 | 0.0 | 0.0 | 0.5 | 0.0 | X | Potentially Pathogenic | Ile501 is located near a hinge in the middle of an α-helix (res. Leu489-Glu519). The sec-butyl side chain of Ile501 is hydrophobically packed with other residues in the inter-helix space (e.g., Leu500, Tyr497, Phe679) in the WT simulations. In the variant simulations, the hydroxyl group of Thr501 forms a hydrogen bond with the backbone atoms of Tyr497 on the same α-helix, which may weaken the α-helix integrity. Additionally, the polar hydroxyl group of Thr501 is not suitable for the hydrophobic inter-helix space, and thus, the residue swap could affect protein folding. However, Ile501 is followed by Gly502, which facilitates a hinge in the middle of the α-helix, making further weakening caused by Thr501 unlikely to be harmful to the α-helix integrity. | ||||||||||||||||
| c.2194A>T | R732W 2D  AIThe SynGAP1 missense variant R732W 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, five tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these computational findings. Thus, the variant is most likely pathogenic based on the current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -11.976 | Likely Pathogenic | 0.252 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -3.57 | Deleterious | 1.000 | Probably Damaging | 0.973 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.1332 | 0.2748 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2300T>C | I767T 2D AIThe SynGAP1 missense variant I767T is listed in ClinVar (ID 1044161.0) with an “Uncertain” status and is not reported in 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, creating a single discordant prediction. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | Uncertain | 1 | -3.749 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.78 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 4.12 | Benign | 0.46 | Tolerated | 3.64 | 6 | 0.1274 | 0.1889 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||
| c.2756A>T | Q919L 2D AIThe SynGAP1 missense variant Q919L is reported in gnomAD (ID 6‑33443308‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. 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 (majority vote) also indicates 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 conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | 6-33443308-A-T | 1 | 6.20e-7 | -4.492 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -2.13 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.40 | Pathogenic | 0.04 | Affected | 4.32 | 4 | 0.0771 | 0.6454 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||
| c.3750G>C | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for Q1250H, 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 | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3750G>T | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1250H, 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 | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.2033G>T | S678I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678I 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), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence (10 benign vs. 3 pathogenic) supports a benign classification. This consensus 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 | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -9.735 | Likely Pathogenic | 0.253 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.3 | -0.01 | Likely Benign | 0.18 | Likely Benign | -0.11 | Likely Benign | 0.119 | Likely Benign | -3.99 | Deleterious | 0.294 | Benign | 0.057 | Benign | 3.45 | Benign | 0.01 | Affected | 0.0941 | 0.5954 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| c.3449C>G | A1150G 2D AIThe SynGAP1 A1150G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.089 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -2.37 | Neutral | 0.983 | Probably Damaging | 0.818 | Possibly Damaging | 2.32 | Pathogenic | 0.09 | Tolerated | 0.2263 | 0.4741 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3522G>C | E1174D 2D AIThe SynGAP1 missense variant E1174D is reported in gnomAD (variant ID 6-33444557-G-C) and 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 classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) 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 | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | 6-33444557-G-C | 1 | 6.20e-7 | -4.257 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.19 | Neutral | 0.002 | Benign | 0.006 | Benign | 5.45 | Benign | 0.36 | Tolerated | 4.32 | 2 | 0.1557 | 0.4226 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||
| c.3522G>T | E1174D 2D AIThe SynGAP1 missense change E1174D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as benign. No tool predicts pathogenicity. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a “Likely Benign” verdict, while AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, every available prediction supports a benign effect, and this conclusion is consistent with the lack of a ClinVar 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 | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -4.257 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.19 | Neutral | 0.002 | Benign | 0.006 | Benign | 5.45 | Benign | 0.36 | Tolerated | 4.32 | 2 | 0.1557 | 0.4226 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.41C>G | P14R 2D AIThe SynGAP1 missense variant P14R 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 high‑accuracy consensus methods give a benign verdict: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No result is available from Foldetta, so its folding‑stability assessment is not considered. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of any ClinVar 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | -2.794 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.183 | Likely Benign | 0.13 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 4.20 | Benign | 0.00 | Affected | 0.1597 | 0.3536 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.1014C>A | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. 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 Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | 0.080 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 0.1584 | 0.5397 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1014C>G | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. 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 Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | 0.080 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 0.1584 | 0.5397 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2023A>C | N675H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Predictions that are inconclusive are Foldetta and premPS. High‑accuracy methods give a benign result from AlphaMissense‑Optimized, a benign consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and an uncertain result from Foldetta. Taken together, the majority of evidence points to a benign impact, and this 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 | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -5.593 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 3.06 | Destabilizing | 1.1 | -0.16 | Likely Benign | 1.45 | Ambiguous | 0.56 | Ambiguous | 0.186 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.929 | Probably Damaging | 3.39 | Benign | 0.04 | Affected | 0.1478 | 0.7478 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.241C>A | L81M 2D AIThe SynGAP1 missense variant L81M is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33425849‑C‑A). 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, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.502033 | Binding | 0.291 | 0.878 | 0.250 | 6-33425849-C-A | 1 | 6.20e-7 | -5.351 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.27 | Neutral | 0.789 | Possibly Damaging | 0.165 | Benign | 3.95 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0692 | 0.2432 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||
| c.2760A>C | Q920H 2D AIThe SynGAP1 missense variant Q920H 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 annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.771 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.79 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1419 | 0.4334 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2760A>T | Q920H 2D AIThe SynGAP1 missense variant Q920H 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 annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.771 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.79 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1419 | 0.4334 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3073C>G | Q1025E 2D AIThe SynGAP1 missense variant Q1025E 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, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates 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 | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -3.010 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.60 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.1391 | 0.2269 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3238G>C | A1080P 2D AIThe SynGAP1 missense variant A1080P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A1080P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -2.429 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.15 | Neutral | 0.996 | Probably Damaging | 0.833 | Possibly Damaging | 3.96 | Benign | 0.02 | Affected | 0.1884 | 0.5324 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.8G>A | R3K 2D AIThe SynGAP1 missense variant R3K 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -4.378 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.45 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 0.5842 | 0.4564 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.2287C>T | L763F 2D  AIThe SynGAP1 missense variant L763F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant. There is no ClinVar entry to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -4.127 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.71 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.39 | Pathogenic | 0.19 | Tolerated | 0.0584 | 0.3140 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| 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.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.2543G>T | G848V 2D AIThe SynGAP1 missense variant G848V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443095‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | 6-33443095-G-T | 1 | 6.20e-7 | -4.445 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1184 | 0.4336 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.2624C>T | A875V 2D AIThe SynGAP1 missense variant A875V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -4.946 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.17 | Neutral | 0.991 | Probably Damaging | 0.904 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 0.1099 | 0.6605 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.83C>T | S28F 2D AIThe SynGAP1 missense variant S28F 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 | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.548 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.13 | Neutral | 0.009 | Benign | 0.002 | Benign | 4.13 | Benign | 0.05 | Affected | 0.0748 | 0.5340 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.169C>G | L57V 2D AIThe SynGAP1 missense variant L57V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -3.598 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.14 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.1533 | 0.4006 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1904A>C | N635T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635T 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b; polyPhen‑2 HumVar, however, classifies it as benign. 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. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and FoldX and premPS also yield uncertain results. Overall, the majority of evidence (five benign vs. four pathogenic) supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -11.705 | Likely Pathogenic | 0.256 | Likely Benign | Likely Benign | 1.50 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.97 | Ambiguous | 0.81 | Ambiguous | 0.240 | Likely Benign | -5.58 | Deleterious | 0.536 | Possibly Damaging | 0.184 | Benign | 2.98 | Benign | 0.04 | Affected | 0.1206 | 0.4032 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.2293A>T | S765C 2D AIThe SynGAP1 missense variant S765C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for S765C, and this conclusion does not contradict any existing ClinVar annotation (none is present). 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 | -6.875 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.12 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 4.05 | Benign | 0.07 | Tolerated | 0.0893 | 0.6309 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| 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.3821G>A | R1274H 2D AIThe SynGAP1 missense variant R1274H (ClinVar ID 2803246.0) is classified as Benign in ClinVar and is present in gnomAD (ID 6‑33447869‑G‑A). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. No Foldetta stability prediction is available for this residue. Overall, the majority of conventional tools predict pathogenicity, and the high‑accuracy AlphaMissense‑Optimized result is benign, leaving the evidence mixed. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, contradicting its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | Likely Benign | 1 | 6-33447869-G-A | 4 | 2.58e-6 | -5.259 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -3.20 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2201 | 0.0936 | 0 | 2 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||
| c.49T>C | S17P 2D AIThe SynGAP1 missense variant S17P 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. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -3.251 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.65 | Neutral | 0.212 | Benign | 0.010 | Benign | 4.01 | Benign | 0.00 | Affected | 0.2406 | 0.6473 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.71T>G | V24G 2D  AIThe SynGAP1 missense variant V24G is not reported in ClinVar (ClinVar status: not present) 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT 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 benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.673 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -1.67 | Neutral | 0.026 | Benign | 0.049 | Benign | 3.77 | Benign | 0.00 | Affected | 0.2081 | 0.3105 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1672C>A | H558N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H558N missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, ESM1b, and FATHMM. Uncertain results come from premPS and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely 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 absence of a ClinVar classification. Thus, the variant is most likely benign. 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 | -9.523 | Likely Pathogenic | 0.257 | Likely Benign | Likely Benign | -0.22 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.30 | Likely Benign | 0.98 | Ambiguous | 0.433 | Likely Benign | -4.58 | Deleterious | 0.388 | Benign | 0.327 | Benign | -1.25 | Pathogenic | 0.14 | Tolerated | 0.1466 | 0.1281 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.2611C>G | H871D 2D AIThe SynGAP1 missense variant H871D 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 | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.263 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -0.51 | Neutral | 0.016 | Benign | 0.026 | Benign | 2.80 | Benign | 0.31 | Tolerated | 0.2271 | 0.1617 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2645G>T | G882V 2D AIThe SynGAP1 missense variant G882V 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, 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 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 | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -5.893 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -2.41 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.06 | Pathogenic | 0.02 | Affected | 0.1178 | 0.4717 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2693C>G | S898C 2D AIThe SynGAP1 missense variant S898C is catalogued in gnomAD (ID 6‑33443245‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while ESM1b remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus also indicates benign. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, did not return a result for this variant, so its stability impact is unavailable. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with ClinVar, which currently has no classification for S898C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | 6-33443245-C-G | 1 | 6.20e-7 | -7.007 | In-Between | 0.257 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.43 | Neutral | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 2.43 | Pathogenic | 0.01 | Affected | 4.32 | 4 | 0.1487 | 0.6166 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2837G>A | G946E 2D AIThe SynGAP1 missense variant G946E is listed in ClinVar (ID 1299783.0) as benign and is present in gnomAD (6‑33443389‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, SIFT, and ESM1b predict 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 unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | Benign | 3 | 6-33443389-G-A | 13 | 8.05e-6 | -8.793 | Likely Pathogenic | 0.257 | Likely Benign | Likely Benign | 0.341 | Likely Benign | -0.51 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 4.58 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1691 | 0.4859 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||
| c.3907G>T | G1303C 2D AIThe SynGAP1 missense variant G1303C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -5.286 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.377 | Likely Benign | -2.49 | Neutral | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 2.76 | Benign | 0.02 | Affected | 0.1319 | 0.3681 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3923G>T | R1308L 2D AIThe SynGAP1 missense variant R1308L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | -1.838 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.360 | Likely Benign | -4.04 | Deleterious | 0.982 | Probably Damaging | 0.982 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | 0.1751 | 0.4930 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3002T>A | L1001H 2D AIThe SynGAP1 missense variant L1001H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -3.119 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -1.02 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.1141 | 0.0958 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3056G>A | R1019H 2D AIThe SynGAP1 missense variant R1019H is listed in ClinVar (ID 1195115.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443608‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for R1019H, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Conflicting | 2 | 6-33443608-G-A | 67 | 4.15e-5 | -4.610 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.95 | Neutral | 0.995 | Probably Damaging | 0.845 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2400 | 0.1903 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.3631A>G | M1211V 2D AIThe SynGAP1 missense variant M1211V is listed in ClinVar as Benign (ClinVar ID 3674914.0) and is present in gnomAD (ID 6‑33446623‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | Benign | 1 | 6-33446623-A-G | 3 | 1.86e-6 | -2.101 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.412 | Likely Benign | -0.29 | Neutral | 0.932 | Possibly Damaging | 0.949 | Probably Damaging | 5.43 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2676 | 0.2720 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||
| c.3748C>A | Q1250K 2D AIThe SynGAP1 missense variant Q1250K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -6.804 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.60 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.81 | Benign | 0.13 | Tolerated | 0.1464 | 0.2484 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||||
| 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.1503T>G | I501M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that are inconclusive or unavailable are FoldX, Foldetta, premPS, and ESM1b. 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 majority of evidence points to a benign impact for I501M. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.452 | In-Between | 0.259 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.2 | -0.19 | Likely Benign | 0.57 | Ambiguous | 0.95 | Ambiguous | 0.294 | Likely Benign | -2.32 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 0.0680 | 0.1589 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| 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.2683A>T | S895C 2D AIThe SynGAP1 missense variant S895C is reported in ClinVar as “None” and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (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, 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 | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -8.006 | Likely Pathogenic | 0.259 | Likely Benign | Likely Benign | 0.182 | Likely Benign | -2.44 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.60 | Benign | 0.08 | Tolerated | 0.1072 | 0.6350 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.296A>G | E99G 2D  AIThe SynGAP1 missense variant E99G 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this 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 | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.031 | Likely Benign | 0.259 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -1.69 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.04 | Benign | 0.00 | Affected | 0.3048 | 0.6399 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3221A>T | Q1074L 2D AIThe SynGAP1 missense variant Q1074L 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -3.561 | Likely Benign | 0.259 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.29 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.68 | Benign | 1.00 | Tolerated | 0.0840 | 0.6293 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2381C>G | P794R 2D AIThe SynGAP1 missense variant P794R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P794R, 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 | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -5.136 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.73 | Neutral | 0.918 | Possibly Damaging | 0.522 | Possibly Damaging | 4.25 | Benign | 0.02 | Affected | 0.1467 | 0.3662 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2816C>G | P939R 2D AIThe SynGAP1 missense variant P939R is reported in gnomAD (ID 6‑33443368‑C‑G) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Grouping by consensus, the benign‑predicted tools outnumbered the pathogenic ones by one, but the overall tally favors pathogenicity (5 pathogenic vs 4 benign). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is benign, but the SGM Consensus (a 2‑vs‑2 majority among AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear verdict, and Foldetta data are unavailable. Consequently, the variant is most likely pathogenic according to the available predictions, and this assessment does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | 6-33443368-C-G | 1 | 6.20e-7 | -4.863 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1360 | 0.3336 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3070C>A | L1024I 2D  AIThe SynGAP1 missense variant L1024I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion 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. | Likely Benign | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.794 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.99 | Neutral | 0.959 | Probably Damaging | 0.642 | Possibly Damaging | 2.45 | Pathogenic | 0.11 | Tolerated | 0.0992 | 0.3735 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>C | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>T | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.346T>A | Y116N 2D AIThe SynGAP1 missense variant Y116N 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 | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | -1.706 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.21 | Neutral | 0.137 | Benign | 0.021 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.2592 | 0.0545 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3896T>G | L1299R 2D AIThe SynGAP1 missense variant L1299R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -3.080 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.293 | Likely Benign | -3.75 | Deleterious | 0.971 | Probably Damaging | 0.597 | Possibly Damaging | 2.68 | Benign | 0.01 | Affected | 0.1366 | 0.1147 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.122G>T | R41L 2D AIThe SynGAP1 missense variant R41L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates 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 R41L, 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 | 0.311707 | Structured | 0.431757 | Uncertain | 0.344 | 0.765 | 0.375 | -3.173 | Likely Benign | 0.261 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -0.58 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.2134 | 0.5868 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1508A>T | Q503L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, premPS, Rosetta, and polyPhen‑2 (HumVar). Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, and FATHMM; FoldX is uncertain and therefore not counted. 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 as benign. Overall, the majority of tools (seven versus six) predict pathogenicity, and the high‑accuracy trio is split but leans toward pathogenic. Thus, the variant is most likely pathogenic based on current 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 Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -8.203 | Likely Pathogenic | 0.261 | Likely Benign | Likely Benign | -0.56 | Ambiguous | 0.2 | -0.07 | Likely Benign | -0.32 | Likely Benign | 0.24 | Likely Benign | 0.711 | Likely Pathogenic | -6.29 | Deleterious | 0.911 | Possibly Damaging | 0.369 | Benign | -1.52 | Pathogenic | 0.05 | Affected | 0.0715 | 0.3578 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.1994A>G | Y665C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665C is listed in ClinVar with no assertion (status: None) and is present in gnomAD (ID 6‑33441253‑A‑G). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also unavailable. Overall, the evidence is mixed, but the majority of high‑confidence tools lean toward a benign interpretation. Thus, the variant is most likely benign based on current predictions, and this does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | 6-33441253-A-G | 1 | 6.20e-7 | -9.007 | Likely Pathogenic | 0.261 | Likely Benign | Likely Benign | 1.05 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.33 | Ambiguous | 1.12 | Destabilizing | 0.210 | Likely Benign | -3.22 | Deleterious | 1.000 | Probably Damaging | 0.981 | Probably Damaging | 3.45 | Benign | 0.14 | Tolerated | 3.38 | 28 | 0.2562 | 0.2019 | -2 | 0 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.3331A>C | K1111Q 2D AIThe SynGAP1 missense variant K1111Q 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 classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign; Foldetta results are not available. Overall, the consensus of available predictions indicates that K1111Q 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 | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -3.687 | Likely Benign | 0.261 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.80 | Neutral | 0.666 | Possibly Damaging | 0.267 | Benign | 2.66 | Benign | 0.31 | Tolerated | 0.4577 | 0.1714 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3878A>G | D1293G 2D  AIThe SynGAP1 missense variant D1293G 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools 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 results are unavailable. Overall, the balance of evidence (5 benign vs 4 pathogenic predictions, with the most accurate tool indicating benign) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -3.060 | Likely Benign | 0.261 | Likely Benign | Likely Benign | 0.332 | Likely Benign | -4.91 | Deleterious | 0.872 | Possibly Damaging | 0.399 | Benign | 2.19 | Pathogenic | 0.00 | Affected | 0.3022 | 0.3944 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3100C>T | P1034S 2D AIThe SynGAP1 missense variant P1034S 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for P1034S, 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 | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -3.730 | Likely Benign | 0.262 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -2.28 | Neutral | 0.011 | Benign | 0.015 | Benign | 2.44 | Pathogenic | 0.05 | Affected | 0.3044 | 0.5853 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3124C>G | Q1042E 2D AIThe SynGAP1 missense variant Q1042E 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 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 | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.231 | Likely Benign | 0.262 | Likely Benign | Likely Benign | 0.267 | Likely Benign | -1.12 | Neutral | 0.224 | Benign | 0.077 | Benign | 5.44 | Benign | 0.15 | Tolerated | 0.2042 | 0.3276 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3737A>C | K1246T 2D AIThe SynGAP1 missense variant K1246T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification for K1246T, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -1.970 | Likely Benign | 0.263 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -2.19 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 0.2032 | 0.2065 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.3980C>A | P1327H 2D AIThe SynGAP1 missense variant P1327H is reported in gnomAD (ID 6‑33451854‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-A | -5.496 | Likely Benign | 0.263 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.49 | Neutral | 0.998 | Probably Damaging | 0.953 | Probably Damaging | 4.09 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1559 | 0.3932 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| 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.3875T>C | L1292P 2D AISynGAP1 missense variant L1292P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑to‑2 split and is therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. With half the tools indicating benign and half indicating pathogenic, the overall computational evidence is ambiguous. Consequently, the variant is neither clearly benign nor pathogenic based on current predictions, and there is no ClinVar entry to contradict this uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -3.761 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -4.58 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 0.3855 | 0.1220 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.502C>T | H168Y 2D AIThe SynGAP1 missense variant H168Y is listed in ClinVar (ID 956914.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | Benign | 1 | -8.914 | Likely Pathogenic | 0.264 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.53 | Neutral | 0.192 | Benign | 0.062 | Benign | 4.18 | Benign | 0.01 | Affected | 4.32 | 3 | 0.0695 | 0.4657 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| 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.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. 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 | Uncertain | 1 | 6-33438843-T-C | 3 | 1.86e-6 | -5.056 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.2 | 0.35 | Likely Benign | -0.03 | Likely Benign | 0.47 | Likely Benign | 0.203 | Likely Benign | -3.81 | Deleterious | 0.993 | Probably Damaging | 0.993 | Probably Damaging | 3.32 | Benign | 0.05 | Affected | 3.37 | 35 | 0.2071 | 0.4650 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||
| c.163C>G | Q55E 2D AIThe SynGAP1 missense variant Q55E 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), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while SIFT uniquely predicts pathogenic. ESM1b 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 reinforce this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also indicates likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with 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 | -7.361 | In-Between | 0.265 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.98 | Neutral | 0.064 | Benign | 0.184 | Benign | 3.89 | Benign | 0.00 | Affected | 0.1380 | 0.2632 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| 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.3112A>G | T1038A 2D AIThe SynGAP1 missense variant T1038A 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, whereas 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -3.544 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.79 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.81 | Benign | 0.15 | Tolerated | 0.3429 | 0.3983 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3277C>G | Q1093E 2D AIThe SynGAP1 missense change Q1093E is not reported in ClinVar and is absent from gnomAD. In silico assessment shows unanimous benign predictions: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” The protein‑folding stability predictor Foldetta was not available for this variant. Overall, the evidence strongly supports a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -3.104 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.59 | Neutral | 0.112 | Benign | 0.041 | Benign | 2.78 | Benign | 0.07 | Tolerated | 0.1514 | 0.3717 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3865A>G | K1289E 2D  AIThe SynGAP1 missense variant K1289E 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. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely benign. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.088 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.19 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.62 | Benign | 0.04 | Affected | 0.3559 | 0.0514 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.631A>G | S211G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211G 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, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, and ESM1b; Rosetta is uncertain. High‑accuracy methods give a benign result for AlphaMissense‑Optimized and for Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic). No evidence from ClinVar contradicts these predictions. Overall, the balance of evidence—including the unanimous benign calls from the high‑accuracy tools—suggests that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.895 | Likely Pathogenic | 0.265 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.42 | Likely Benign | 1.07 | Destabilizing | 0.067 | Likely Benign | -3.17 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 3.92 | Benign | 0.07 | Tolerated | 0.2560 | 0.4337 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.127G>C | G43R 2D  AIThe SynGAP1 missense variant G43R 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 G43R, 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 | 0.308712 | Structured | 0.431462 | Uncertain | 0.396 | 0.762 | 0.375 | -2.104 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.26 | Neutral | 0.870 | Possibly Damaging | 0.500 | Possibly Damaging | 4.22 | Benign | 0.00 | Affected | 0.1025 | 0.3645 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3149G>A | G1050E 2D AIThe SynGAP1 missense variant G1050E 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only ESM1b 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. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -8.175 | Likely Pathogenic | 0.266 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.28 | Neutral | 0.411 | Benign | 0.171 | Benign | 2.50 | Benign | 0.08 | Tolerated | 0.1418 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3638A>C | N1213T 2D AIThe SynGAP1 missense variant N1213T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446630‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0968 | 0.4546 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||
| c.1070A>C | H357P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools give uncertain results: Foldetta (protein‑folding stability) and ESM1b. 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 evidence points to a benign effect. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. 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 | -7.953 | In-Between | 0.267 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.9 | 3.52 | Destabilizing | 1.85 | Ambiguous | -0.06 | Likely Benign | 0.197 | Likely Benign | -2.70 | Deleterious | 0.936 | Possibly Damaging | 0.469 | Possibly Damaging | 4.18 | Benign | 0.17 | Tolerated | 0.2433 | 0.4468 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||
| c.115T>C | Y39H 2D  AIThe SynGAP1 missense variant Y39H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -3.166 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.08 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0.2569 | 0.0843 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.181G>C | E61Q 2D  AIThe SynGAP1 missense variant E61Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for E61Q, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -5.443 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.41 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.1344 | 0.5617 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.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.2681G>C | G894A 2D AIThe SynGAP1 missense variant G894A is reported in gnomAD (ID 6‑33443233‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, 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 Benign | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | 6-33443233-G-C | 1 | 6.20e-7 | -3.997 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -1.26 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.69 | Benign | 0.97 | Tolerated | 4.32 | 4 | 0.3857 | 0.4670 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2843G>A | G948D 2D AIThe SynGAP1 missense variant G948D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -8.423 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.279 | Likely Benign | 0.15 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.55 | Benign | 0.11 | Tolerated | 0.1871 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>C | Q1021P 2D AIThe SynGAP1 missense variant Q1021P 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 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 Q1021P, 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 | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -3.522 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -2.11 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.56 | Benign | 0.02 | Affected | 0.2022 | 0.4789 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3244C>G | Q1082E 2D AIThe SynGAP1 missense variant Q1082E is reported in gnomAD (ID 6‑33443796‑C‑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 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 results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | 6-33443796-C-G | -3.437 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.87 | Neutral | 0.112 | Benign | 0.026 | Benign | 4.19 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.1485 | 0.3227 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||
| c.3295T>C | Y1099H 2D AIThe SynGAP1 missense variant Y1099H is reported in gnomAD (variant ID 6-33443847‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443847-T-C | 1 | 6.49e-7 | -3.620 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.50 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.76 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2453 | 0.0735 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||
| c.3416A>G | Q1139R 2D AIThe SynGAP1 missense variant Q1139R 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 and 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. 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 | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -4.249 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.315 | Likely Benign | -1.91 | Neutral | 0.126 | Benign | 0.138 | Benign | 5.47 | Benign | 0.00 | Affected | 0.1342 | 0.2405 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.382C>A | P128T 2D AIThe SynGAP1 missense variant P128T is listed in ClinVar with an “Uncertain” status (ClinVar ID 2801315.0) and is present in gnomAD (ID 6‑33432247‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) 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 “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | Uncertain | 1 | 6-33432247-C-A | 1 | 6.20e-7 | -4.217 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.19 | Benign | 0.35 | Tolerated | 3.74 | 4 | 0.2023 | 0.4053 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||
| c.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, 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. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.777 | Likely Pathogenic | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0.0913 | 0.5859 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | ||||||||||||||
| c.916G>C | V306L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V306L missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain 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 likely benign, and Foldetta is inconclusive. 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 existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | -3.633 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 2.14 | Destabilizing | 0.2 | 1.47 | Ambiguous | 1.81 | Ambiguous | 0.75 | Ambiguous | 0.161 | Likely Benign | -1.01 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.76 | Pathogenic | 0.21 | Tolerated | 0.0823 | 0.4117 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1121C>T | S374F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S374F missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign outcome, while Foldetta’s stability analysis remains uncertain. Overall, the majority of evidence points to a benign effect, 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 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | -7.907 | In-Between | 0.268 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.8 | 0.60 | Ambiguous | 0.58 | Ambiguous | -0.19 | Likely Benign | 0.202 | Likely Benign | -1.19 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 6.29 | Benign | 0.00 | Affected | 0.1045 | 0.6427 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| 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.2926T>G | F976V 2D  AIThe SynGAP1 missense variant F976V 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -3.328 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -1.32 | Neutral | 0.451 | Benign | 0.157 | Benign | 4.18 | Benign | 0.23 | Tolerated | 0.2696 | 0.2902 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3088C>T | H1030Y 2D AIThe SynGAP1 missense variant H1030Y 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for H1030Y, 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -5.365 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -1.73 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.73 | Benign | 0.01 | Affected | 0.0874 | 0.4236 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3097T>C | S1033P 2D AIThe SynGAP1 missense variant S1033P is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. 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: 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 overall assessment. Based on the consensus of all available predictions, 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 | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -2.046 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.05 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.68 | Benign | 0.27 | Tolerated | 0.1889 | 0.5486 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.311G>A | R104H 2D AIThe SynGAP1 missense variant R104H is reported in gnomAD (variant ID 6‑33432176‑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 it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available for this variant. Overall, the preponderance of evidence indicates that R104H 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 | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | 6-33432176-G-A | 2 | 1.24e-6 | -4.126 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -1.42 | Neutral | 0.066 | Benign | 0.004 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2431 | 0.2102 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||||
| c.382C>T | P128S 2D AIThe SynGAP1 missense variant P128S is reported in gnomAD (variant ID 6‑33432247‑C‑T) but has no ClinVar entry. 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 it as pathogenic, creating a single discordant prediction. 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 (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 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 | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | 6-33432247-C-T | 1 | 6.20e-7 | -3.234 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -1.35 | Neutral | 0.734 | Possibly Damaging | 0.243 | Benign | 4.20 | Benign | 0.24 | Tolerated | 3.74 | 4 | 0.3893 | 0.3697 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.65G>A | R22K 2D AIThe SynGAP1 missense variant R22K is reported in gnomAD (variant ID 6‑33420329‑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 it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. 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 points to a benign effect for R22K, 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 | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420329-G-A | -4.736 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -0.12 | Neutral | 0.140 | Benign | 0.067 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.6413 | 0.5384 | Strenghten | 2 | 3 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||
| c.783C>A | D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E 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 consensus from AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) both indicate a benign outcome, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the majority of evidence points to a benign impact. This assessment is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Based on the predictions, the variant is most likely benign, and this does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -2.646 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.8 | 0.79 | Ambiguous | 1.12 | Ambiguous | -0.03 | Likely Benign | 0.377 | Likely Benign | 0.20 | Neutral | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.88 | Benign | 1.00 | Tolerated | 0.0963 | 0.4359 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.783C>G | D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E 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. 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) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are uncertain. Overall, the majority of evidence points to a benign impact, which is consistent with the absence of a ClinVar claim and gnomAD observation. 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 | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -2.646 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.8 | 0.79 | Ambiguous | 1.12 | Ambiguous | -0.03 | Likely Benign | 0.377 | Likely Benign | 0.20 | Neutral | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.88 | Benign | 1.00 | Tolerated | 0.0963 | 0.4359 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.80C>G | P27R 2D AIThe SynGAP1 missense variant P27R 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 P27R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.260 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.28 | Neutral | 0.972 | Probably Damaging | 0.954 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | 0.1744 | 0.4203 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.1606T>G | L536V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536V is listed in ClinVar (ID 1690714.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | Uncertain | 1 | -9.014 | Likely Pathogenic | 0.269 | Likely Benign | Likely Benign | 1.25 | Ambiguous | 0.3 | 1.22 | Ambiguous | 1.24 | Ambiguous | 1.20 | Destabilizing | 0.586 | Likely Pathogenic | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.09 | Tolerated | 3.37 | 34 | 0.1591 | 0.3565 | 2 | 1 | 0.4 | -14.03 | 204.7 | 26.4 | 0.2 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects. | ||||||||||||||||
| c.2507G>A | S836N 2D AIThe SynGAP1 missense variant S836N 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 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 is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -3.881 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.75 | Neutral | 0.901 | Possibly Damaging | 0.636 | Possibly Damaging | 2.89 | Benign | 0.85 | Tolerated | 0.1053 | 0.3831 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3115A>C | I1039L 2D  AIThe SynGAP1 missense variant I1039L is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. 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 benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -2.035 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.14 | Neutral | 0.264 | Benign | 0.048 | Benign | 2.82 | Benign | 0.98 | Tolerated | 0.1057 | 0.4605 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3295T>A | Y1099N 2D AIThe SynGAP1 missense variant Y1099N 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, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.329 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -1.01 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.83 | Benign | 0.16 | Tolerated | 0.2121 | 0.0935 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.347A>C | Y116S 2D AIThe SynGAP1 missense variant Y116S is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. 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 view: 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 consensus of all available predictions strongly suggests that Y116S 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 | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | -0.249 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.05 | Neutral | 0.033 | Benign | 0.013 | Benign | 4.31 | Benign | 0.58 | Tolerated | 0.5111 | 0.1694 | Weaken | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||||
| c.3704T>A | M1235K 2D  AIThe SynGAP1 missense variant M1235K 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 substitution 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 tools, including the high‑accuracy methods, supports a benign classification. This prediction 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 | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -6.348 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -2.37 | Neutral | 0.270 | Benign | 0.089 | Benign | 2.66 | Benign | 0.00 | Affected | 0.1282 | 0.0656 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||
| c.91C>G | R31G 2D AIThe SynGAP1 missense variant R31G 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 R31G, 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 | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.259 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.77 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 0.3389 | 0.3942 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.1042G>C | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, 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. 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. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of 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 | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | 0.072 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 0.1088 | 0.4953 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1042G>T | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, 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. 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. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of 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 | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | 0.072 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 0.1088 | 0.4953 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| 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.2185A>G | N729D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729D is predicted to be benign by all available 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) also indicates “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact on protein stability. ClinVar contains no entry for this variant, and it is not listed in gnomAD. Based on the collective 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 | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.117 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.03 | Likely Benign | 0.2 | 0.10 | Likely Benign | 0.07 | Likely Benign | 0.14 | Likely Benign | 0.054 | Likely Benign | -1.22 | Neutral | 0.390 | Benign | 0.144 | Benign | 3.41 | Benign | 0.55 | Tolerated | 0.1931 | 0.2250 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.2310G>C | Q770H 2D AIThe SynGAP1 missense variant Q770H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for Q770H. 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 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>T | Q770H 2D AIThe SynGAP1 missense variant Q770H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>A | D868E 2D AIThe SynGAP1 missense variant D868E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>G | D868E 2D AIThe SynGAP1 missense variant D868E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>T | H1030L 2D AIThe SynGAP1 missense variant H1030L 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 SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also 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 the majority of prediction tools and the high‑accuracy methods indicates that H1030L is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.513 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -2.35 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.02 | Affected | 0.0968 | 0.5710 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.83C>A | S28Y 2D AIThe SynGAP1 missense variant S28Y 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 unavailable. Overall, the majority of evidence points to a benign effect. There is no conflict with 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 Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.521 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.94 | Neutral | 0.009 | Benign | 0.001 | Benign | 4.13 | Benign | 0.05 | Affected | 0.0895 | 0.5067 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2722C>G | Q908E 2D AIThe SynGAP1 missense variant Q908E 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. 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 status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q908E, 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 | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.178 | Likely Benign | 0.271 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -1.14 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.58 | Benign | 1.00 | Tolerated | 0.1255 | 0.1886 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.613A>T | I205F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205F missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen‑2 HumVar all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. Uncertain results from Foldetta, premPS, ESM1b, and Rosetta are treated as unavailable. 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, while Foldetta remains uncertain. Overall, the consensus of the majority of tools 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 | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -7.913 | In-Between | 0.271 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.3 | 0.89 | Ambiguous | 0.60 | Ambiguous | 0.52 | Ambiguous | 0.113 | Likely Benign | -1.80 | Neutral | 0.838 | Possibly Damaging | 0.368 | Benign | 4.08 | Benign | 0.10 | Tolerated | 0.0461 | 0.2205 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2101C>A | P701T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a tolerated change. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive, and FoldX alone is uncertain, so these results are treated as unavailable. Overall, the evidence strongly supports a benign effect for P701T, 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 | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -6.920 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 1.61 | Ambiguous | 0.0 | 0.11 | Likely Benign | 0.86 | Ambiguous | -0.18 | Likely Benign | 0.144 | Likely Benign | -0.43 | Neutral | 0.084 | Benign | 0.050 | Benign | 3.44 | Benign | 0.70 | Tolerated | 0.1398 | 0.4160 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.2756A>G | Q919R 2D AIThe SynGAP1 missense variant Q919R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.636 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.96 | Neutral | 0.961 | Probably Damaging | 0.596 | Possibly Damaging | 2.65 | Benign | 0.85 | Tolerated | 0.1558 | 0.2305 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3185G>A | G1062E 2D AIThe SynGAP1 missense variant G1062E 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -8.185 | Likely Pathogenic | 0.272 | Likely Benign | Likely Benign | 0.383 | Likely Benign | -1.02 | Neutral | 0.126 | Benign | 0.041 | Benign | 4.10 | Benign | 0.01 | Affected | 0.1490 | 0.4069 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>A | P1146T 2D AIThe SynGAP1 missense variant P1146T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus call of “Likely Benign.” In contrast, PROVEAN, polyPhen‑2 HumDiv, and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are not available. Overall, the majority of evidence points to a benign effect for P1146T, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.494 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 0.454 | Likely Benign | -4.11 | Deleterious | 0.573 | Possibly Damaging | 0.334 | Benign | 5.51 | Benign | 0.00 | Affected | 0.1478 | 0.5789 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.1048G>A | V350M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350M 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, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, premPS, ESM1b) 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 benign, and Foldetta as benign. Taken together, the majority of evidence supports a benign classification. 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. | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -7.493 | In-Between | 0.273 | Likely Benign | Likely Benign | -0.65 | Ambiguous | 0.1 | 0.40 | Likely Benign | -0.13 | Likely Benign | 0.69 | Ambiguous | 0.075 | Likely Benign | -1.95 | Neutral | 0.868 | Possibly Damaging | 0.383 | Benign | 1.63 | Pathogenic | 0.06 | Tolerated | 0.1005 | 0.4359 | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||
| c.2164A>T | S722C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the majority of individual predictors and the high‑accuracy methods lean toward a benign impact, with only the SGM Consensus suggesting pathogenicity. Thus, the variant is most likely benign based on the available predictions, 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 | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -8.060 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.0 | -0.23 | Likely Benign | -0.01 | Likely Benign | 0.28 | Likely Benign | 0.362 | Likely Benign | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 2.46 | Pathogenic | 0.05 | Affected | 0.1132 | 0.4306 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.2614T>C | S872P 2D AIThe SynGAP1 missense variant S872P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 predicts Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence indicates that S872P 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 | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.291 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.2321 | 0.5581 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3246G>C | Q1082H 2D AIThe SynGAP1 missense variant Q1082H 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. 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.4779 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3246G>T | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is listed in gnomAD (ID 6‑33443798‑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 report benign or tolerated outcomes, while only SIFT predicts 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 further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | 6-33443798-G-T | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.4779 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3271C>A | L1091I 2D AIThe SynGAP1 missense variant L1091I is reported in gnomAD (ID 6‑33443823‑C‑A) but has no ClinVar entry. Across the available in‑silico predictors, every tool classified the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all returned benign scores. No tool predicted pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this benign 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. Overall, the computational evidence strongly supports a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | 6-33443823-C-A | -4.304 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.66 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.55 | Benign | 0.13 | Tolerated | 3.77 | 5 | 0.1073 | 0.3911 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.373C>A | P125T 2D AIThe SynGAP1 missense variant P125T 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN 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 annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -4.780 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -3.78 | Deleterious | 0.036 | Benign | 0.014 | Benign | 2.85 | Benign | 0.01 | Affected | 0.1502 | 0.4995 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3980C>G | P1327R 2D AIThe SynGAP1 missense variant P1327R is reported in gnomAD (variant ID 6‑33451854‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-G | -4.724 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.95 | Neutral | 0.994 | Probably Damaging | 0.937 | Probably Damaging | 4.12 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1442 | 0.2798 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3983G>A | R1328Q 2D AIThe SynGAP1 missense variant R1328Q is listed in ClinVar (ID 1805359.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451857‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | Uncertain | 3 | 6-33451857-G-A | 35 | 1.49e-4 | -2.921 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.799 | Possibly Damaging | 0.098 | Benign | 4.12 | Benign | 0.03 | Affected | 3.77 | 5 | 0.3503 | 0.1775 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.496G>C | A166P 2D AIThe SynGAP1 missense variant A166P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for A166P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -9.665 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -2.04 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.99 | Benign | 0.02 | Affected | 0.1861 | 0.3668 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.1328G>T | G443V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443V 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. 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, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Overall, the majority of evidence points to a benign impact for G443V, 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 | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -4.130 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.2 | -2.19 | Stabilizing | -1.01 | Ambiguous | 0.21 | Likely Benign | 0.099 | Likely Benign | -2.90 | Deleterious | 0.585 | Possibly Damaging | 0.195 | Benign | 3.36 | Benign | 0.12 | Tolerated | 0.1089 | 0.3375 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| 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.14G>T | R5L 2D AIThe SynGAP1 missense variant R5L 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 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 | 0.595080 | Disordered | 0.547847 | Binding | 0.363 | 0.920 | 0.750 | -3.297 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -0.06 | Neutral | 0.030 | Benign | 0.003 | Benign | 4.14 | Benign | 0.00 | Affected | 0.2256 | 0.5914 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2216A>T | E739V 2D  AIThe SynGAP1 missense variant E739V 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM 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 preponderance of evidence from both general and high‑accuracy predictors points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | Uncertain | 1 | -3.136 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.86 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | 4.32 | 2 | 0.0953 | 0.7431 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.2855G>A | G952D 2D AIThe SynGAP1 missense variant G952D is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -7.299 | In-Between | 0.274 | Likely Benign | Likely Benign | 0.241 | Likely Benign | -0.75 | Neutral | 0.033 | Benign | 0.015 | Benign | 3.20 | Benign | 0.05 | Affected | 0.1928 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2941G>A | G981S 2D  AIThe SynGAP1 missense variant G981S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is not available for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign effect. 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 Benign | 0.798249 | Disordered | 0.970320 | Binding | 0.275 | 0.897 | 0.625 | -2.749 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -0.57 | Neutral | 0.979 | Probably Damaging | 0.907 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 0.2566 | 0.5470 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3422C>A | P1141Q 2D  AIThe SynGAP1 missense variant P1141Q 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), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points 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. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.331 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.72 | Deleterious | 0.074 | Benign | 0.047 | Benign | 0.97 | Pathogenic | 0.00 | Affected | 0.1449 | 0.5186 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3685C>G | Q1229E 2D AIThe SynGAP1 missense change Q1229E lies in a coiled‑coil domain. ClinVar has no entry for this variant, and it is absent from gnomAD. 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; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance 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. | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -7.319 | In-Between | 0.274 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -1.75 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.80 | Pathogenic | 0.17 | Tolerated | 0.1184 | 0.1336 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3762G>C | E1254D 2D AIThe SynGAP1 missense change E1254D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Overall, the majority of evidence indicates that E1254D is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -4.648 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.44 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.62 | Benign | 0.51 | Tolerated | 0.1402 | 0.3471 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3762G>T | E1254D 2D AIThe SynGAP1 missense change E1254D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E1254D is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -4.648 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.44 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.62 | Benign | 0.51 | Tolerated | 0.1402 | 0.3471 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.497C>T | A166V 2D AIThe SynGAP1 missense variant A166V 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 the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of 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 | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.689 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -1.09 | Neutral | 0.141 | Benign | 0.091 | Benign | 4.07 | Benign | 0.02 | Affected | 0.1027 | 0.4281 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.169C>A | L57I 2D AIThe SynGAP1 missense variant L57I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for the L57I variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.254060 | Structured | 0.481044 | Uncertain | 0.554 | 0.642 | 0.000 | -3.681 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.07 | Neutral | 0.458 | Possibly Damaging | 0.745 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0973 | 0.4106 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.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.3857A>T | E1286V 2D AIThe SynGAP1 missense variant E1286V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑benign/2‑pathogenic split. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.195 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.259 | Likely Benign | -3.90 | Deleterious | 0.960 | Probably Damaging | 0.679 | Possibly Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.0828 | 0.5614 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.787G>C | V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.599 | Likely Benign | 0.275 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.40 | Likely Benign | 0.66 | Ambiguous | 0.453 | Likely Benign | -1.26 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.85 | Benign | 0.18 | Tolerated | 0.0759 | 0.3950 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.787G>T | V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.599 | Likely Benign | 0.275 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.40 | Likely Benign | 0.66 | Ambiguous | 0.453 | Likely Benign | -1.26 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.85 | Benign | 0.18 | Tolerated | 0.0759 | 0.3950 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.2268G>C | Q756H 2D AIThe SynGAP1 missense variant Q756H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.625 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.05 | Affected | 0.1545 | 0.4404 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2268G>T | Q756H 2D AIThe SynGAP1 missense variant Q756H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none is present). 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 | -4.625 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.05 | Affected | 0.1545 | 0.4404 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2369C>A | T790N 2D  AIThe SynGAP1 missense variant T790N is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33442921‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable, and Foldetta results are not reported. Overall, the majority of conventional tools (5 pathogenic vs. 4 benign) lean toward a pathogenic interpretation, while the single high‑accuracy tool suggests benign. The variant’s ClinVar status remains uncertain, so there is no contradiction with the current clinical 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 | Conflicting | 3 | 6-33442921-C-A | 69 | 4.28e-5 | -5.243 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -2.54 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.27 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.1446 | 0.4653 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||
| c.3888G>C | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.299 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3888G>T | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.493 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1888A>C | I630L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I630L is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33440940‑A‑C). 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. Tools that predict a pathogenic effect are ESM1b and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; the SGM Consensus remains unavailable. Based on the overall 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. | GAP | 0.040537 | Structured | 0.036106 | Uncertain | 0.966 | 0.236 | 0.000 | 6-33440940-A-C | -8.949 | Likely Pathogenic | 0.277 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.0 | 0.23 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | 0.165 | Likely Benign | -1.30 | Neutral | 0.102 | Benign | 0.108 | Benign | -0.81 | Pathogenic | 0.27 | Tolerated | 3.37 | 34 | 0.0688 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||
| c.2120C>T | A707V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707V variant is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (variant ID 6‑33441585‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign classification. Only three tools—Rosetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar—predict pathogenicity, while Foldetta reports an uncertain stability change. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for A707V, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. 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 | 6-33441585-C-T | 1 | 6.20e-7 | -6.479 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.05 | Likely Benign | 0.0 | 2.17 | Destabilizing | 1.11 | Ambiguous | -0.30 | Likely Benign | 0.212 | Likely Benign | -1.62 | Neutral | 0.991 | Probably Damaging | 0.912 | Probably Damaging | 3.45 | Benign | 1.00 | Tolerated | 3.50 | 9 | 0.0794 | 0.4048 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.2936T>A | F979Y 2D  AIThe SynGAP1 missense variant F979Y is not reported in ClinVar and is absent from gnomAD. All available 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 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 method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.977500 | Binding | 0.274 | 0.889 | 0.625 | -3.420 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.26 | Neutral | 0.451 | Benign | 0.285 | Benign | 4.18 | Benign | 0.06 | Tolerated | 0.1451 | 0.2843 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3335A>G | E1112G 2D AIThe SynGAP1 missense variant E1112G is reported in gnomAD (ID 6‑33443887‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN and SIFT. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a “Likely Benign” classification. AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates the variant is most likely benign, and this assessment 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 | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | 6-33443887-A-G | 1 | 6.73e-7 | -3.459 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.58 | Deleterious | 0.058 | Benign | 0.015 | Benign | 2.70 | Benign | 0.01 | Affected | 4.32 | 2 | 0.2795 | 0.6220 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.3406C>G | Q1136E 2D AIThe SynGAP1 missense variant Q1136E is catalogued in gnomAD (ID 6‑33443958‑C‑G) and has no ClinVar entry. All evaluated in silico predictors uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments 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 method, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443958-C-G | 4 | 2.71e-6 | -6.677 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -1.13 | Neutral | 0.022 | Benign | 0.026 | Benign | 5.46 | Benign | 0.11 | Tolerated | 4.32 | 2 | 0.1487 | 0.2886 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.345G>C | Q115H 2D AIThe SynGAP1 missense variant Q115H 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. 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. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q115H, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.888 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.08 | Benign | 0.17 | Tolerated | 0.1248 | 0.3383 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.345G>T | Q115H 2D AIThe SynGAP1 missense variant Q115H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods points to a benign classification for Q115H, 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.888 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.08 | Benign | 0.17 | Tolerated | 0.1248 | 0.3383 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.44C>A | A15E 2D  AIThe SynGAP1 missense variant A15E is reported in gnomAD (ID 6‑33420308‑C‑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 it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | 6-33420308-C-A | -3.423 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.169 | Likely Benign | 0.46 | Neutral | 0.406 | Benign | 0.040 | Benign | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1563 | 0.1908 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.133A>G | N45D 2D AIThe SynGAP1 missense variant N45D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; no Foldetta stability result is available. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification for this 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 | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -3.340 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.37 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.2234 | 0.4999 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2339C>G | S780C 2D AIThe SynGAP1 missense variant S780C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442891‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome; ESM1b is inconclusive and therefore treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are not reported and thus unavailable. Based on the collective predictions, the variant is most likely benign, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | Uncertain | 4 | 6-33442891-C-G | 16 | 9.94e-6 | -7.603 | In-Between | 0.278 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.41 | Neutral | 0.065 | Benign | 0.043 | Benign | 2.59 | Benign | 0.10 | Tolerated | 3.64 | 6 | 0.1063 | 0.6581 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| c.389A>T | Q130L 2D AIThe SynGAP1 missense variant Q130L 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 Q130L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.643 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -1.63 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.11 | Benign | 0.02 | Affected | 0.0975 | 0.5286 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.1097C>T | T366I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366I is reported in gnomAD (6‑33438002‑C‑T) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). 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, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No other tools provide conclusive evidence for pathogenicity. **Based on the aggregate 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 | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | 6-33438002-C-T | 1 | 6.20e-7 | -4.921 | Likely Benign | 0.279 | Likely Benign | Likely Benign | -0.62 | Ambiguous | 0.1 | -0.31 | Likely Benign | -0.47 | Likely Benign | -0.14 | Likely Benign | 0.058 | Likely Benign | -1.22 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.77 | Pathogenic | 0.26 | Tolerated | 3.38 | 23 | 0.1062 | 0.6215 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| 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.1315C>G | L439V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (8 benign vs. 5 pathogenic) favor a benign classification, and this consensus does not contradict the absence of ClinVar evidence. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -6.340 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 2.34 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.37 | Destabilizing | 0.91 | Ambiguous | 0.121 | Likely Benign | -1.13 | Neutral | 0.976 | Probably Damaging | 0.941 | Probably Damaging | 3.36 | Benign | 0.12 | Tolerated | 0.1272 | 0.2628 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1697A>G | K566R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K566R missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, predictions are split evenly between benign and pathogenic, with no clear consensus. The variant is therefore most likely of uncertain significance; 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 | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | -8.493 | Likely Pathogenic | 0.279 | Likely Benign | Likely Benign | 1.26 | Ambiguous | 0.5 | 1.04 | Ambiguous | 1.15 | Ambiguous | 0.29 | Likely Benign | 0.555 | Likely Pathogenic | -2.39 | Neutral | 0.996 | Probably Damaging | 0.990 | Probably Damaging | -0.79 | Pathogenic | 0.43 | Tolerated | 0.4093 | 0.1099 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.2588T>A | L863Q 2D AIThe SynGAP1 missense variant L863Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence from multiple independent predictors points to a benign classification for L863Q, 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 | 0.594839 | Binding | 0.267 | 0.795 | 0.250 | -6.334 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -0.68 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 4.02 | Benign | 0.23 | Tolerated | 0.1100 | 0.1305 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3944G>C | W1315S 2D  AIThe SynGAP1 missense variant W1315S 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 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.896 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.115 | Benign | 0.057 | Benign | 4.26 | Benign | 0.13 | Tolerated | 0.3974 | 0.1211 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.50C>G | S17C 2D AIThe SynGAP1 missense variant S17C 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) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -4.364 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.17 | Neutral | 0.486 | Possibly Damaging | 0.048 | Benign | 3.99 | Benign | 0.00 | Affected | 0.1226 | 0.6721 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.1049T>C | V350A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V350A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), premPS, PROVEAN, ESM1b, and FATHMM. Stability‑based methods FoldX, Rosetta, and Foldetta give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools. Therefore, the variant is most likely pathogenic based on the current computational evidence, 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 | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -8.323 | Likely Pathogenic | 0.280 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.0 | 1.97 | Ambiguous | 1.70 | Ambiguous | 2.07 | Destabilizing | 0.096 | Likely Benign | -2.73 | Deleterious | 0.435 | Benign | 0.115 | Benign | 1.64 | Pathogenic | 0.55 | Tolerated | 0.3207 | 0.2967 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.2651G>T | R884L 2D AIThe SynGAP1 missense variant R884L 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 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 | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -3.482 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.08 | Neutral | 0.300 | Benign | 0.191 | Benign | 2.63 | Benign | 0.24 | Tolerated | 0.1809 | 0.4177 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2675C>G | S892C 2D AIThe SynGAP1 missense variant S892C 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 S892C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -6.855 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 0.1189 | 0.5323 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>T | Q920L 2D AIThe SynGAP1 missense variant Q920L 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 (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -4.048 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.181 | Likely Benign | -2.36 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0774 | 0.5995 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3229A>G | T1077A 2D AIThe SynGAP1 missense variant T1077A is catalogued in gnomAD (ID 6‑33443781‑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 consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports 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 | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443781-A-G | -3.303 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.60 | Neutral | 0.288 | Benign | 0.194 | Benign | 4.25 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3373 | 0.4393 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.3790G>T | G1264C 2D AIThe SynGAP1 missense variant G1264C 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 G1264C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -5.666 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.03 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.74 | Benign | 0.09 | Tolerated | 0.1087 | 0.3691 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.53A>C | Y18S 2D AIThe SynGAP1 missense variant Y18S is reported in gnomAD (ID 6‑33420317‑A‑C) 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, while only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus 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 for Y18S. This conclusion is consistent with the absence of a pathogenic ClinVar 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 | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420317-A-C | -1.061 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.50 | Neutral | 0.389 | Benign | 0.036 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4961 | 0.2640 | -2 | -3 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||
| c.235A>G | N79D 2D AIThe SynGAP1 missense variant N79D 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.457064 | Uncertain | 0.290 | 0.876 | 0.375 | -3.746 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.021 | Likely Benign | -0.92 | Neutral | 0.371 | Benign | 0.018 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1893 | 0.2535 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.281C>G | P94R 2D AIThe SynGAP1 missense variant P94R 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment 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 | 0.671169 | Disordered | 0.570978 | Binding | 0.350 | 0.869 | 0.625 | -3.272 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.31 | Neutral | 0.110 | Benign | 0.012 | Benign | 4.11 | Benign | 0.00 | Affected | 0.1445 | 0.2780 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3085C>G | Q1029E 2D AIThe SynGAP1 missense variant Q1029E is reported in gnomAD (ID 6‑33443637‑C‑G) but has no ClinVar entry. 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 it as pathogenic, creating a single discordant call. 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 predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | 6-33443637-C-G | 17 | 1.05e-5 | -3.660 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.92 | Neutral | 0.625 | Possibly Damaging | 0.258 | Benign | 2.83 | Benign | 0.26 | Tolerated | 3.77 | 5 | 0.1327 | 0.2433 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.3988C>G | Q1330E 2D AIThe SynGAP1 missense variant Q1330E 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 reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.428 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.12 | Neutral | 0.613 | Possibly Damaging | 0.240 | Benign | 3.98 | Benign | 0.06 | Tolerated | 0.1346 | 0.2409 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.533A>G | K178R 2D AIThe SynGAP1 missense variant K178R is reported in gnomAD (ID 6‑33435175‑A‑G) but has no ClinVar entry. Functional 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 consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for K178R, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | 6-33435175-A-G | 1 | 6.20e-7 | -4.398 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.62 | Neutral | 0.905 | Possibly Damaging | 0.393 | Benign | 3.98 | Benign | 0.14 | Tolerated | 3.54 | 6 | 0.5403 | 0.1131 | Weaken | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||
| c.1501A>C | I501L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, Rosetta, Foldetta, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain or inconclusive results are reported for FoldX, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign, all supporting a non‑deleterious effect. Based on the preponderance of benign predictions and the concordant high‑accuracy tools, 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 | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.348 | In-Between | 0.282 | Likely Benign | Likely Benign | 0.78 | Ambiguous | 0.2 | -0.34 | Likely Benign | 0.22 | Likely Benign | 0.86 | Ambiguous | 0.219 | Likely Benign | -1.92 | Neutral | 0.930 | Possibly Damaging | 0.985 | Probably Damaging | 3.51 | Benign | 0.05 | Affected | 0.0817 | 0.2261 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| 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.2481C>G | I827M 2D AIThe SynGAP1 missense variant I827M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that 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 | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -4.910 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.61 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.13 | Tolerated | 0.0642 | 0.2560 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.290A>G | E97G 2D AIThe SynGAP1 missense variant E97G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.609018 | Binding | 0.340 | 0.867 | 0.625 | -2.752 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.03 | Neutral | 0.947 | Possibly Damaging | 0.727 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.3286 | 0.6569 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3514C>A | H1172N 2D AIThe SynGAP1 missense variant H1172N 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 classify the change as tolerated or benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this 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 | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.770 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.255 | Likely Benign | -1.14 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 5.59 | Benign | 0.04 | Affected | 0.1512 | 0.2158 | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||||||||||
| c.3811G>C | E1271Q 2D AIThe SynGAP1 missense variant E1271Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. This conclusion is not contradicted by ClinVar, which has no entry for this variant. 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 | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.085 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -2.40 | Neutral | 0.951 | Possibly Damaging | 0.617 | Possibly Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.0955 | 0.5470 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1586T>A | I529N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529N 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: 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 calculations, predicts a benign effect. Taken together, the preponderance of evidence from both general and high‑accuracy predictors 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 | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | -4.478 | Likely Benign | 0.283 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.2 | -0.05 | Likely Benign | 0.04 | Likely Benign | 0.46 | Likely Benign | 0.378 | Likely Benign | -0.31 | Neutral | 0.997 | Probably Damaging | 0.952 | Probably Damaging | -1.24 | Pathogenic | 0.20 | Tolerated | 0.0722 | 0.0700 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1102C>A | P368T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P368T missense variant is not listed 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 effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes 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 a tie (2 benign, 2 pathogenic) and thus inconclusive, and Foldetta remains uncertain. Overall, the predictions are evenly split between benign and pathogenic, providing no definitive classification. The variant’s status does not contradict ClinVar, which has no entry for it. 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 | -5.308 | Likely Benign | 0.284 | Likely Benign | Likely Benign | 1.95 | Ambiguous | 0.6 | 1.61 | Ambiguous | 1.78 | Ambiguous | 0.45 | Likely Benign | 0.188 | Likely Benign | -5.43 | Deleterious | 0.941 | Possibly Damaging | 0.527 | Possibly Damaging | 1.72 | Pathogenic | 0.01 | Affected | 0.1983 | 0.6155 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1964T>G | L655R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655R 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, and the majority of consensus methods (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all score the variant as benign. The only inconclusive result comes from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce this benign prediction: 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) also predicts benign. Thus, based on the available predictions, 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 | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | -4.848 | Likely Benign | 0.284 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.0 | 0.54 | Ambiguous | 0.07 | Likely Benign | -0.09 | Likely Benign | 0.160 | Likely Benign | 0.46 | Neutral | 0.006 | Benign | 0.001 | Benign | 3.50 | Benign | 0.60 | Tolerated | 0.1589 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.3965C>A | A1322D 2D  AIThe SynGAP1 missense variant A1322D is catalogued in gnomAD (ID 6‑33451839‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—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. Grouping by consensus, all available tools fall into the benign category, with no tools indicating pathogenicity. 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.” Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no result for this variant, so its status is unavailable. Based on the collective evidence, 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 | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-A | -5.744 | Likely Benign | 0.284 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.70 | Neutral | 0.013 | Benign | 0.004 | Benign | 4.17 | Benign | 0.45 | Tolerated | 3.77 | 5 | 0.2246 | 0.3134 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.133A>C | N45H 2D AIThe SynGAP1 missense variant N45H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns 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 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 | -2.620 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.62 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | 0.2009 | 0.8046 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.1750A>C | I584L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I584L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the preponderance 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. | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | -8.266 | Likely Pathogenic | 0.285 | Likely Benign | Likely Benign | -0.18 | Likely Benign | 0.1 | -0.30 | Likely Benign | -0.24 | Likely Benign | 0.84 | Ambiguous | 0.420 | Likely Benign | -1.74 | Neutral | 0.008 | Benign | 0.046 | Benign | -1.23 | Pathogenic | 0.18 | Tolerated | 0.0927 | 0.2817 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.199C>G | L67V 2D AIThe SynGAP1 missense variant L67V 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. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the L67V substitution, 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 | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.617 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -0.31 | Neutral | 0.458 | Possibly Damaging | 0.364 | Benign | 4.15 | Benign | 0.00 | Affected | 0.1138 | 0.2817 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2245C>G | R749G 2D AIThe SynGAP1 missense variant R749G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R749G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -3.045 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -1.03 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.68 | Benign | 0.02 | Affected | 0.3690 | 0.4196 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| 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.2512A>C | N838H 2D AIThe SynGAP1 missense variant N838H is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. 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) 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 does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -6.650 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.1417 | 0.5303 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2687G>T | G896V 2D AIThe SynGAP1 missense variant G896V is reported in gnomAD (6-33443239-G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign outcome. Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for G896V, 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 | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | 6-33443239-G-T | 1 | 6.20e-7 | -2.936 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.165 | Likely Benign | -1.96 | Neutral | 0.997 | Probably Damaging | 0.912 | Probably Damaging | 2.46 | Pathogenic | 0.30 | Tolerated | 4.32 | 4 | 0.1264 | 0.4026 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.2839G>T | G947W 2D  AIThe SynGAP1 missense variant G947W has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -10.819 | Likely Pathogenic | 0.285 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -1.21 | Neutral | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 4.90 | Benign | 0.01 | Affected | 0.0914 | 0.4059 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3100C>A | P1034T 2D AIThe SynGAP1 missense variant P1034T is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict a pathogenic outcome: SIFT and FATHMM. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 predictions support 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 | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.367 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -2.00 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0.1518 | 0.6620 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3262A>G | S1088G 2D AIThe SynGAP1 missense variant S1088G is listed in ClinVar (ID 2742833.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus 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 | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | Uncertain | 1 | -5.034 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -1.83 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2541 | 0.5170 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3280T>C | S1094P 2D AIThe SynGAP1 missense variant S1094P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1094P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -2.430 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.31 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.46 | Pathogenic | 0.13 | Tolerated | 0.2322 | 0.6099 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3515A>G | H1172R 2D AIThe SynGAP1 missense variant H1172R 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. 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that H1172R is most likely benign, and this conclusion does not contradict any ClinVar status, as none is assigned to the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -0.848 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.08 | Neutral | 0.001 | Benign | 0.004 | Benign | 5.46 | Benign | 0.05 | Affected | 0.1547 | 0.2219 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||
| c.8G>C | R3T 2D  AIThe SynGAP1 missense variant R3T 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this 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 | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -3.693 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.55 | Neutral | 0.208 | Benign | 0.018 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1809 | 0.5145 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| 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.1225A>C | M409L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The only inconclusive result is from premPS, which is marked uncertain and does not influence the overall benign consensus. High‑accuracy assessments further support a benign outcome: 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 collective evidence, 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 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -6.809 | Likely Benign | 0.286 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.2 | -0.08 | Likely Benign | -0.06 | Likely Benign | 0.51 | Ambiguous | 0.199 | Likely Benign | -0.84 | Neutral | 0.206 | Benign | 0.324 | Benign | 4.21 | Benign | 0.57 | Tolerated | 0.1299 | 0.4411 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1225A>T | M409L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The only inconclusive result is premPS, which is listed as uncertain and does not influence the overall assessment. High‑accuracy methods confirm the benign prediction: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also classifies it as benign. Based on the collective 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 | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -6.809 | Likely Benign | 0.286 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.2 | -0.08 | Likely Benign | -0.06 | Likely Benign | 0.51 | Ambiguous | 0.199 | Likely Benign | -0.84 | Neutral | 0.206 | Benign | 0.324 | Benign | 4.21 | Benign | 0.57 | Tolerated | 0.1299 | 0.4411 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.2648T>G | L883R 2D AIThe SynGAP1 missense variant L883R 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for the L883R variant, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | -3.026 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.83 | Neutral | 0.934 | Possibly Damaging | 0.435 | Benign | 2.73 | Benign | 0.11 | Tolerated | 0.1237 | 0.1147 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3512C>G | A1171G 2D AIThe SynGAP1 missense variant A1171G (Ala→Gly at residue 1171) is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, and 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 a likely benign outcome, while Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.487 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -0.60 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.38 | Benign | 0.08 | Tolerated | 0.1957 | 0.3201 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3886G>C | E1296Q 2D AIThe SynGAP1 missense variant E1296Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, 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 | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.510 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.148 | Likely Benign | -2.11 | Neutral | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.0978 | 0.5736 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3950G>T | G1317V 2D AIThe SynGAP1 missense variant G1317V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | -4.604 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -2.99 | Deleterious | 0.004 | Benign | 0.004 | Benign | 4.05 | Benign | 0.00 | Affected | 0.1132 | 0.3635 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.815G>A | R272Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R272Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437720‑G‑A). Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and PROVEAN. Those that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; and Foldetta predicts benign. With the majority of high‑accuracy tools supporting a benign effect, the variant is most likely benign, which does not contradict its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | Uncertain | 2 | 6-33437720-G-A | 14 | 8.67e-6 | -9.559 | Likely Pathogenic | 0.286 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.15 | Likely Benign | 0.44 | Likely Benign | 1.00 | Destabilizing | 0.321 | Likely Benign | -1.81 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.88 | Pathogenic | 0.03 | Affected | 3.38 | 19 | 0.2966 | 0.1973 | 1 | 1 | 1.0 | -28.06 | 255.7 | 52.9 | 0.0 | 0.0 | -0.2 | 0.1 | X | Uncertain | The guanidinium group of Arg272, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), is stably maintained in an upright and outward position via stacking with the indole ring of the Trp362 side chain in another β strand (res. Thr359-Pro364). In the WT simulations, Arg272 forms hydrogen bonds with the glycine-rich Ω loop residues (res. Val365-Pro398, e.g., Gly380) and creates a salt bridge with the carboxylate group of the Asp304 side chain.In the variant simulations, the carboxamide group of the Gln272 side chain does not stack with the indole ring of Trp362 as stably as the guanidinium group of Arg272 in the WT. Consequently, the Gln272 side chain is freer to interact with the loop residues than Arg272, potentially negatively affecting the dynamic SynGAP-membrane association. Additionally, Arg272 faces the RasGTPase interface, so the residue swap could impact the SynGAP-Ras complex formation and GTPase activation. | ||||||||||||||
| c.887C>G | S296C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296C 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are 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 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -7.842 | In-Between | 0.286 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.18 | Likely Benign | 0.09 | Likely Benign | 0.361 | Likely Benign | -1.46 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.05 | Affected | 0.1052 | 0.6052 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| 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.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.3155G>A | G1052E 2D AIThe SynGAP1 missense variant G1052E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.869 | Likely Pathogenic | 0.287 | Likely Benign | Likely Benign | 0.448 | Likely Benign | -0.64 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 3.90 | Benign | 0.12 | Tolerated | 0.1405 | 0.3873 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3890G>C | R1297T 2D AIThe SynGAP1 missense variant R1297T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: seven tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, FATHMM) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. 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. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.941 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -2.95 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.49 | Pathogenic | 0.08 | Tolerated | 0.1634 | 0.2972 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.86T>A | M29K 2D AIThe SynGAP1 missense variant M29K is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency or clinical annotation. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts 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 further support a benign interpretation: 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 collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -2.514 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -0.88 | Neutral | 0.018 | Benign | 0.184 | Benign | 4.27 | Benign | 0.00 | Affected | 0.2019 | 0.1312 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2201C>G | P734R 2D AIThe SynGAP1 missense variant P734R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -6.099 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -3.00 | Deleterious | 0.984 | Probably Damaging | 0.682 | Possibly Damaging | 2.71 | Benign | 0.07 | Tolerated | 0.1664 | 0.2464 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.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.269T>C | V90A 2D AIThe SynGAP1 missense variant V90A 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 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant 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 is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that V90A 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 | 0.570702 | Disordered | 0.542047 | Binding | 0.343 | 0.873 | 0.500 | -0.984 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.27 | Neutral | 0.053 | Benign | 0.008 | Benign | 4.11 | Benign | 0.00 | Affected | 0.3129 | 0.3154 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.1081C>G | Q361E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Taken together, the majority of evidence supports a benign impact for Q361E, 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 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -7.544 | In-Between | 0.289 | Likely Benign | Likely Benign | 0.29 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.66 | Ambiguous | 0.21 | Likely Benign | 0.153 | Likely Benign | -0.89 | Neutral | 0.969 | Probably Damaging | 0.930 | Probably Damaging | 1.70 | Pathogenic | 0.26 | Tolerated | 0.1217 | 0.3018 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| 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.1106C>T | T369I 2D AIThe SynGAP1 missense variant T369I 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive evidence. 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; there is no conflict with ClinVar status, which contains no entry for this variant. 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 | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -6.759 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.8 | 1.41 | Ambiguous | 1.01 | Ambiguous | -0.08 | Likely Benign | 0.078 | Likely Benign | -2.37 | Neutral | 0.396 | Benign | 0.142 | Benign | 1.72 | Pathogenic | 0.13 | Tolerated | 0.1106 | 0.7207 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.2040G>C | E680D 2D AIThe SynGAP1 missense variant E680D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce 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) is 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -5.019 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.8 | 0.27 | Likely Benign | 0.24 | Likely Benign | -0.10 | Likely Benign | 0.121 | Likely Benign | -0.64 | Neutral | 0.906 | Possibly Damaging | 0.295 | Benign | 3.66 | Benign | 0.32 | Tolerated | 0.2199 | 0.5208 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2040G>T | E680D 2D AIThe SynGAP1 missense variant E680D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional 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 predict benign or likely benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, representing the sole discordant prediction. High‑accuracy assessments reinforce 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) is benign. No prediction or folding‑stability result is missing or inconclusive. **Based on the aggregate 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 | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -5.019 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.8 | 0.27 | Likely Benign | 0.24 | Likely Benign | -0.10 | Likely Benign | 0.121 | Likely Benign | -0.64 | Neutral | 0.906 | Possibly Damaging | 0.295 | Benign | 3.66 | Benign | 0.32 | Tolerated | 0.2199 | 0.5208 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.241C>G | L81V 2D AIThe SynGAP1 missense variant L81V is not reported in ClinVar and is absent from gnomAD. 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 variant 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 status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for L81V, 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 | 0.632174 | Disordered | 0.502033 | Binding | 0.291 | 0.878 | 0.250 | -5.207 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.51 | Neutral | 0.178 | Benign | 0.014 | Benign | 4.04 | Benign | 0.00 | Affected | 0.1423 | 0.2653 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1402A>C | M468L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L 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, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments—all available—show benign predictions: AlphaMissense‑Optimized (Benign), SGM‑Consensus (Likely Benign), and Foldetta (Benign). Based on the overall consensus of the majority of tools and the high‑accuracy 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 | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.412 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 0.1564 | 0.4408 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1402A>T | M468L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 outcome. 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 | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.412 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 0.1564 | 0.4408 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.2969C>T | S990F 2D AIThe SynGAP1 missense variant S990F 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, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for S990F. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.253 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.65 | Deleterious | 0.710 | Possibly Damaging | 0.272 | Benign | 2.75 | Benign | 0.00 | Affected | 0.0814 | 0.6021 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3164G>A | G1055E 2D AIThe SynGAP1 missense variant G1055E is catalogued in gnomAD (variant ID 6‑33443716‑G‑A) but has no ClinVar entry. In silico prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | 6-33443716-G-A | 1 | 6.21e-7 | -10.951 | Likely Pathogenic | 0.290 | Likely Benign | Likely Benign | 0.320 | Likely Benign | -0.03 | Neutral | 0.901 | Possibly Damaging | 0.456 | Possibly Damaging | 3.30 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1525 | 0.4459 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| 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.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.2502G>A | M834I 2D AIThe SynGAP1 missense variant M834I 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. 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 | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2502G>C | M834I 2D AIThe SynGAP1 missense variant M834I is listed in ClinVar (ID 3007819.0) with an uncertain significance designation and is not reported 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 predict benign. Only SIFT classifies the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the collective predictions indicate that M834I 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 | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | Uncertain | 1 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2502G>T | M834I 2D AIThe SynGAP1 missense variant M834I 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2740G>A | D914N 2D AIThe SynGAP1 missense variant D914N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.859 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -1.22 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 0.1770 | 0.7848 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2938C>A | H980N 2D AIThe SynGAP1 missense variant H980N is not reported in ClinVar or gnomAD. Functional prediction tools largely agree on a benign effect. Benign calls come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus confirms a benign result; Foldetta data are unavailable, so no additional stability evidence is considered. Overall, the computational evidence indicates that H980N is most likely benign, 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 Benign | 0.812494 | Disordered | 0.974598 | Binding | 0.309 | 0.892 | 0.625 | -4.728 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.07 | Neutral | 0.451 | Benign | 0.209 | Benign | 4.17 | Benign | 0.00 | Affected | 0.2346 | 0.3638 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3724G>C | E1242Q 2D AIThe SynGAP1 missense variant E1242Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Consequently, the aggregate evidence favors a benign effect for E1242Q, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.557691 | Disordered | 0.456349 | Uncertain | 0.870 | 0.549 | 0.500 | -7.036 | In-Between | 0.291 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.33 | Neutral | 0.969 | Probably Damaging | 0.843 | Possibly Damaging | 2.21 | Pathogenic | 0.00 | Affected | 0.0763 | 0.3666 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3117T>G | I1039M 2D AIThe SynGAP1 missense variant I1039M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for I1039M, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -3.444 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.38 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.68 | Benign | 0.16 | Tolerated | 0.0926 | 0.4392 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3197C>G | P1066R 2D AIThe SynGAP1 missense variant P1066R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -5.154 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.176 | Likely Benign | -2.89 | Deleterious | 0.992 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1523 | 0.4742 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>T | S1108I 2D AIThe SynGAP1 missense variant S1108I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443875‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no reported result for this variant. Overall, the balance of evidence (five benign versus four pathogenic predictions) suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | Uncertain | 1 | 6-33443875-G-T | -3.666 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -3.73 | Deleterious | 0.971 | Probably Damaging | 0.604 | Possibly Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.0949 | 0.4602 | -2 | -1 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.273G>C | E91D 2D AIThe SynGAP1 missense variant E91D is reported in gnomAD (variant ID 6‑33425881‑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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | 6-33425881-G-C | 1 | 6.20e-7 | -3.160 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.84 | Neutral | 0.880 | Possibly Damaging | 0.636 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2000 | 0.5219 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.273G>T | E91D 2D AIThe SynGAP1 missense variant E91D 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 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 | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | -3.160 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.84 | Neutral | 0.880 | Possibly Damaging | 0.636 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2000 | 0.5219 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.2939A>T | H980L 2D AIThe SynGAP1 missense variant H980L 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 the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this 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 | 0.812494 | Disordered | 0.974598 | Binding | 0.309 | 0.892 | 0.625 | -1.984 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -1.98 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1488 | 0.5538 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3803T>G | L1268R 2D AIThe SynGAP1 missense change L1268R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all support a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy tools reinforce the benign assessment: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are not available, so they do not influence the interpretation. Overall, the preponderance of evidence points to a benign effect for L1268R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -7.010 | In-Between | 0.293 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.1135 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.850C>A | L284I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, 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, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of predictions, including the high‑accuracy methods, support a benign classification. This consensus 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 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -5.853 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | 1.22 | Ambiguous | 0.86 | Ambiguous | 0.49 | Likely Benign | 0.364 | Likely Benign | -1.51 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.88 | Pathogenic | 0.13 | Tolerated | 0.0738 | 0.3006 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.961C>G | R321G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, while the high‑accuracy subset is mixed, with one benign, one pathogenic, and one uncertain result. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -10.554 | Likely Pathogenic | 0.293 | Likely Benign | Likely Benign | 0.90 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.59 | Ambiguous | 0.49 | Likely Benign | 0.430 | Likely Benign | -3.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.04 | Affected | 0.3224 | 0.2898 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.3782G>A | S1261N 2D AIThe SynGAP1 missense variant S1261N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports 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 S1261N, 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 | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.850 | Likely Benign | 0.294 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.92 | Neutral | 0.959 | Probably Damaging | 0.551 | Possibly Damaging | 2.23 | Pathogenic | 0.12 | Tolerated | 0.0917 | 0.2820 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.3868A>T | R1290W 2D AIThe SynGAP1 missense variant R1290W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence from multiple independent predictors points to a benign impact for R1290W, 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 | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -5.672 | Likely Benign | 0.294 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -5.15 | Deleterious | 0.994 | Probably Damaging | 0.920 | Probably Damaging | 2.58 | Benign | 0.00 | Affected | 0.0992 | 0.2724 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2194A>G | R732G 2D AIThe SynGAP1 R732G missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33441659‑A‑G). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, while the most accurate single predictor (AlphaMissense‑Optimized) suggests a benign outcome. Given the lack of ClinVar evidence, there is no contradiction; 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. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | 6-33441659-A-G | 1 | 6.20e-7 | -9.348 | Likely Pathogenic | 0.295 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.98 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.56 | Benign | 0.03 | Affected | 3.59 | 7 | 0.3080 | 0.2942 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2854G>C | G952R 2D AIThe SynGAP1 missense variant G952R is not reported in ClinVar and is absent from gnomAD. 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 as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G952R 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 | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.974 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.077 | Benign | 0.011 | Benign | 3.20 | Benign | 0.02 | Affected | 0.1145 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3263G>C | S1088T 2D AIThe SynGAP1 missense variant S1088T 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 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 | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.569 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -1.32 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.71 | Benign | 0.04 | Affected | 0.2048 | 0.6514 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3284C>A | P1095Q 2D AIThe SynGAP1 missense variant P1095Q 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 it as pathogenic, but this is the sole discordant call. 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 predicts benign, and the SGM‑Consensus 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 points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.171 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.64 | Neutral | 0.922 | Possibly Damaging | 0.441 | Benign | 2.85 | Benign | 0.45 | Tolerated | 0.1573 | 0.5519 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2252C>G | P751R 2D AIThe SynGAP1 missense variant P751R is catalogued in gnomAD (ID 6‑33441717‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN and polyPhen‑2 HumDiv. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | 6-33441717-C-G | 1 | 6.20e-7 | -5.646 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.157 | Likely Benign | -2.61 | Deleterious | 0.719 | Possibly Damaging | 0.295 | Benign | 2.68 | Benign | 0.06 | Tolerated | 3.99 | 5 | 0.1390 | 0.3644 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| 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.2677C>G | Q893E 2D AIThe SynGAP1 missense variant Q893E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact all converge on a benign interpretation: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.888 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.67 | Neutral | 0.421 | Benign | 0.181 | Benign | 2.76 | Benign | 0.06 | Tolerated | 0.1535 | 0.2555 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2791C>A | L931I 2D AIThe SynGAP1 missense variant L931I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 HumDiv and polyPhen‑2 HumVar both 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 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 multiple prediction algorithms indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.989212 | Binding | 0.335 | 0.856 | 0.375 | -3.813 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.120 | Likely Benign | 0.42 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.58 | Benign | 0.14 | Tolerated | 0.1076 | 0.3540 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2831G>A | G944D 2D AIThe SynGAP1 missense variant G944D 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 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the majority‑vote SGM‑Consensus also indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign classification. Foldetta stability analysis is not available for this residue. Overall, the preponderance of evidence points to a benign impact, and this assessment does not conflict with the absence of a ClinVar claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -7.684 | In-Between | 0.296 | Likely Benign | Likely Benign | 0.421 | Likely Benign | -1.42 | Neutral | 0.224 | Benign | 0.131 | Benign | 3.70 | Benign | 0.00 | Affected | 0.1833 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3917A>T | N1306I 2D AIThe SynGAP1 missense variant N1306I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.234 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -6.15 | Deleterious | 0.890 | Possibly Damaging | 0.761 | Possibly Damaging | 2.56 | Benign | 0.00 | Affected | 0.0837 | 0.6672 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3019A>G | S1007G 2D AIThe SynGAP1 missense variant S1007G 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. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -4.051 | Likely Benign | 0.297 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.49 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.73 | Benign | 0.05 | Affected | 0.2361 | 0.4341 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3176G>A | G1059E 2D AIThe SynGAP1 missense variant G1059E is reported in gnomAD (variant ID 6‑33443728‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—SIFT and ESM1b—predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | 6-33443728-G-A | 1 | 6.22e-7 | -10.459 | Likely Pathogenic | 0.297 | Likely Benign | Likely Benign | 0.390 | Likely Benign | -0.71 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1464 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3905T>G | L1302W 2D AIThe SynGAP1 missense variant L1302W 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is uncertain and not counted. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this is consistent with the SGM Consensus result. Therefore, the variant is most likely pathogenic based on current computational evidence, and this does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -7.133 | In-Between | 0.297 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -4.20 | Deleterious | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 1.49 | Pathogenic | 0.00 | Affected | 0.0671 | 0.2530 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3956C>A | A1319D 2D AIThe SynGAP1 missense variant A1319D is reported in gnomAD (ID 6‑33451830‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319D, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-A | -5.156 | Likely Benign | 0.297 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.85 | Neutral | 0.971 | Probably Damaging | 0.813 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2290 | 0.2702 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.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.2719A>T | S907C 2D AIThe SynGAP1 missense variant S907C is listed in ClinVar as Benign (ClinVar ID 1502069.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification and indicating no contradiction with the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | Likely Benign | 1 | -6.685 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.34 | Neutral | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1023 | 0.5951 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3128G>C | R1043T 2D AIThe SynGAP1 missense variant R1043T 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 the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of 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 | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -3.928 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.463 | Likely Benign | -1.77 | Neutral | 0.001 | Benign | 0.003 | Benign | 5.39 | Benign | 0.00 | Affected | 0.1975 | 0.5513 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3451T>C | S1151P 2D AIThe SynGAP1 missense variant S1151P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, 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. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.031 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.47 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.67 | Benign | 0.11 | Tolerated | 0.1953 | 0.5320 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>T | N1306Y 2D AIThe SynGAP1 missense variant N1306Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -4.193 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.273 | Likely Benign | -5.59 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.0732 | 0.6658 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2272T>C | Y758H 2D AIThe SynGAP1 missense variant Y758H 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 the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.194 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.92 | Neutral | 0.064 | Benign | 0.031 | Benign | 2.71 | Benign | 0.02 | Affected | 0.2519 | 0.0331 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2348T>C | M783T 2D AIThe SynGAP1 missense variant M783T 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 classify the change as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the high‑accuracy consensus points to a benign effect, with no conflict with ClinVar reporting. 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 | -4.064 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -2.08 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 2.69 | Benign | 0.03 | Affected | 0.2217 | 0.2308 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2437C>A | L813M 2D AIThe SynGAP1 missense variant L813M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, 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 a pathogenic effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact 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 | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.893 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.53 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.23 | Tolerated | 0.0814 | 0.3922 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2690C>T | S897L 2D AIThe SynGAP1 missense variant S897L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same four high‑accuracy tools) also as benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.418474 | Uncertain | 0.292 | 0.928 | 0.500 | Uncertain | 1 | -4.034 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -1.71 | Neutral | 0.901 | Possibly Damaging | 0.636 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 0.1280 | 0.5770 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||
| c.2938C>T | H980Y 2D AIThe SynGAP1 missense variant H980Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for H980Y, 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 | 0.812494 | Disordered | 0.974598 | Binding | 0.309 | 0.892 | 0.625 | -4.104 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.12 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.1524 | 0.4706 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.35G>T | S12I 2D AIThe SynGAP1 missense variant S12I 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, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -4.838 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.05 | Neutral | 0.659 | Possibly Damaging | 0.072 | Benign | 4.09 | Benign | 0.00 | Affected | 0.0964 | 0.6082 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3823C>G | R1275G 2D AIThe SynGAP1 missense variant R1275G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for R1275G, 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 | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | -6.302 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -3.58 | Deleterious | 0.800 | Possibly Damaging | 0.277 | Benign | 2.54 | Benign | 0.01 | Affected | 0.3272 | 0.2486 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>A | T1305K 2D  AIThe SynGAP1 missense variant T1305K 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. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for T1305K, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -4.289 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -1.33 | Neutral | 0.027 | Benign | 0.042 | Benign | 2.77 | Benign | 0.01 | Affected | 0.1290 | 0.3532 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.71T>C | V24A 2D AIThe SynGAP1 missense variant V24A 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 predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact for V24A. This prediction 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.980 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.09 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.83 | Benign | 0.00 | Affected | 0.3117 | 0.3350 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.148A>C | I50L 2D AIThe SynGAP1 missense variant I50L is not reported in ClinVar and is absent from gnomAD. 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -3.509 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.73 | Neutral | 0.010 | Benign | 0.004 | Benign | 3.91 | Benign | 0.00 | Affected | 0.0749 | 0.3247 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| 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.1985A>T | Q662L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662L 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, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. 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 (2 benign vs 2 pathogenic). Overall, the majority of evidence supports a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -10.291 | Likely Pathogenic | 0.300 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.0 | 0.12 | Likely Benign | 0.08 | Likely Benign | 0.17 | Likely Benign | 0.186 | Likely Benign | -4.09 | Deleterious | 0.699 | Possibly Damaging | 0.057 | Benign | 3.42 | Benign | 0.10 | Tolerated | 0.1070 | 0.5255 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.2608C>G | L870V 2D AIThe SynGAP1 missense variant L870V is listed in ClinVar (ID 946946.0) with an “Uncertain” status and is not reported in gnomAD. 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 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | Uncertain | 1 | -4.123 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.64 | Benign | 0.12 | Tolerated | 3.88 | 3 | 0.1549 | 0.3977 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.289G>C | E97Q 2D AIThe SynGAP1 missense variant E97Q is reported in gnomAD (ID 6‑33425897‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both consensus and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.609018 | Binding | 0.340 | 0.867 | 0.625 | 6-33425897-G-C | 2 | 1.24e-6 | -3.917 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.32 | Neutral | 0.978 | Probably Damaging | 0.832 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1507 | 0.7874 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.3212G>T | G1071V 2D AIThe SynGAP1 missense variant G1071V is catalogued in gnomAD (ID 6‑33443764‑G‑T) 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 report benign or likely 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 classification. 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, supports a benign interpretation. This prediction 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 Benign | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | 6-33443764-G-T | 3 | 1.87e-6 | -2.901 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -2.42 | Neutral | 0.057 | Benign | 0.022 | Benign | 4.14 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1408 | 0.3634 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.3884A>G | Q1295R 2D AIThe SynGAP1 missense variant Q1295R is catalogued in gnomAD (ID 6‑33447932‑A‑G) but has no ClinVar entry. Functional prediction tools show discordant results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta data are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation, though the presence of several benign predictions and the lack of a ClinVar classification mean the variant’s clinical significance remains uncertain. No contradiction exists with ClinVar status, as no ClinVar claim is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447932-A-G | -3.342 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.351 | Likely Benign | -3.30 | Deleterious | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1432 | 0.1348 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||
| c.3896T>A | L1299H 2D AIThe SynGAP1 missense variant L1299H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -4.586 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.317 | Likely Benign | -3.83 | Deleterious | 0.992 | Probably Damaging | 0.750 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1293 | 0.1273 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.92G>C | R31P 2D AIThe SynGAP1 missense variant R31P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact for R31P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.185 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -1.64 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 0.2220 | 0.5005 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.1498C>A | L500M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The premPS score is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. No other high‑accuracy predictions are available. Overall, the majority of high‑accuracy tools lean toward a benign interpretation, and this assessment does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -9.945 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | -0.09 | Likely Benign | 0.03 | Likely Benign | 0.92 | Ambiguous | 0.590 | Likely Pathogenic | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0710 | 0.2202 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1957C>G | L653V 2D AIThe SynGAP1 missense variant L653V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and premPS, while ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | Uncertain | 1 | -7.050 | In-Between | 0.301 | Likely Benign | Likely Benign | 3.28 | Destabilizing | 0.3 | 2.18 | Destabilizing | 2.73 | Destabilizing | 1.32 | Destabilizing | 0.146 | Likely Benign | -2.25 | Neutral | 0.227 | Benign | 0.039 | Benign | 3.28 | Benign | 0.08 | Tolerated | 0.1436 | 0.3557 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||
| c.2107C>G | L703V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703V 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 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Because the variant is not present in ClinVar or gnomAD, there is no existing clinical classification to contradict. Overall, the majority of predictions and the two high‑accuracy benign assessments suggest the variant is most likely benign, although the Foldetta result indicates a potential pathogenic effect that warrants further functional investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -10.086 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 2.32 | Destabilizing | 0.1 | 2.61 | Destabilizing | 2.47 | Destabilizing | 1.07 | Destabilizing | 0.080 | Likely Benign | -2.22 | Neutral | 0.789 | Possibly Damaging | 0.352 | Benign | 3.19 | Benign | 0.00 | Affected | 0.1383 | 0.2621 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2459A>T | Y820F 2D  AIThe SynGAP1 missense variant Y820F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for Y820F, 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 | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | -4.686 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.67 | Neutral | 0.990 | Probably Damaging | 0.893 | Possibly Damaging | 2.69 | Benign | 0.21 | Tolerated | 0.2398 | 0.2636 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>C | S873T 2D AIThe SynGAP1 missense variant S873T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -6.364 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.77 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.11 | Tolerated | 0.1514 | 0.6288 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2669G>C | R890P 2D AIThe SynGAP1 missense variant R890P is listed in ClinVar (ID 575680.0) as Benign and is present in gnomAD (6‑33443221‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar status, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.531156 | Binding | 0.284 | 0.928 | 0.625 | Likely Benign | 2 | 6-33443221-G-C | 28 | 1.74e-5 | -1.931 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -1.21 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 4.02 | Benign | 0.28 | Tolerated | 4.32 | 4 | 0.2239 | 0.3551 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||
| c.2810A>G | D937G 2D AIThe SynGAP1 missense variant D937G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that D937G is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -0.770 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.817 | Possibly Damaging | 2.82 | Benign | 0.72 | Tolerated | 0.4313 | 0.7006 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2845G>C | G949R 2D AIThe SynGAP1 missense variant G949R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows a split: benign calls come from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, 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. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -7.650 | In-Between | 0.301 | Likely Benign | Likely Benign | 0.317 | Likely Benign | -0.14 | Neutral | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.21 | Pathogenic | 0.01 | Affected | 0.1095 | 0.4569 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.512C>G | A171G 2D AIThe SynGAP1 missense variant A171G 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -4.019 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -1.08 | Neutral | 0.063 | Benign | 0.026 | Benign | 4.14 | Benign | 0.05 | Affected | 0.1767 | 0.3278 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2155A>T | N719Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Rosetta and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also uncertain. Overall, the majority of evaluated tools (7 benign vs 4 pathogenic) support a benign classification. Thus, 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. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -11.005 | Likely Pathogenic | 0.302 | Likely Benign | Likely Benign | -0.38 | Likely Benign | 0.0 | -0.62 | Ambiguous | -0.50 | Ambiguous | 0.33 | Likely Benign | 0.187 | Likely Benign | -4.15 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.09 | Tolerated | 0.0412 | 0.3951 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||
| c.3872T>G | L1291R 2D AIThe SynGAP1 missense variant L1291R is not reported in ClinVar and is present in gnomAD (ID 6‑33447920‑T‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta results are unavailable. Overall, the majority of conventional predictors indicate a pathogenic effect, whereas the single high‑accuracy tool suggests benign. No ClinVar annotation contradicts these findings. Thus, based on the collective evidence, the variant is most likely pathogenic, though the high‑accuracy prediction introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447920-T-G | 1 | 6.44e-7 | -3.977 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.287 | Likely Benign | -4.29 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1160 | 0.1049 | -2 | -3 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.2908G>A | E970K 2D  AIThe SynGAP1 missense variant E970K 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign interpretation, 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 | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | -3.344 | Likely Benign | 0.303 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.24 | Neutral | 0.078 | Benign | 0.042 | Benign | 4.18 | Benign | 0.17 | Tolerated | 0.3372 | 0.7361 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3020G>C | S1007T 2D AIThe SynGAP1 missense variant S1007T is reported in ClinVar as “Not submitted” (no ClinVar entry) and is present in gnomAD (allele ID 6‑33443572‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus as likely benign; Foldetta results are not available. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | 6-33443572-G-C | -4.719 | Likely Benign | 0.303 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.68 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1796 | 0.5550 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.2489C>A | P830Q 2D AIThe SynGAP1 missense variant P830Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 annotation (none is present). 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 | -4.984 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.257 | Likely Benign | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 0.1396 | 0.4741 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2716C>T | L906F 2D AIThe SynGAP1 missense variant L906F 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 the variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -4.700 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.79 | Neutral | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.22 | Pathogenic | 0.18 | Tolerated | 0.0753 | 0.3342 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>A | G943D 2D AIThe SynGAP1 missense variant G943D is not reported in ClinVar and is absent from gnomAD. In silico predictors that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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. Taken together, the overwhelming majority of predictions indicate a benign effect, and this conclusion does not contradict any ClinVar status (none is assigned). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -7.951 | In-Between | 0.304 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.28 | Neutral | 0.224 | Benign | 0.113 | Benign | 2.85 | Benign | 0.11 | Tolerated | 0.1904 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3017A>T | Y1006F 2D AIThe SynGAP1 missense variant Y1006F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -3.362 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.06 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.71 | Benign | 0.10 | Tolerated | 0.2423 | 0.3339 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3944G>T | W1315L 2D  AIThe SynGAP1 missense variant W1315L 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 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.369 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.65 | Neutral | 0.115 | Benign | 0.057 | Benign | 4.29 | Benign | 0.16 | Tolerated | 0.2256 | 0.3338 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||||||||||||
| c.824C>T | P275L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275L is not reported in ClinVar and is absent from gnomAD. In silico predictions cluster into two groups: benign predictions come from REVEL, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of tools predict pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. This prediction does not contradict any ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | -9.785 | Likely Pathogenic | 0.304 | Likely Benign | Likely Benign | 1.63 | Ambiguous | 0.2 | 1.22 | Ambiguous | 1.43 | Ambiguous | 0.29 | Likely Benign | 0.430 | Likely Benign | -6.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.83 | Pathogenic | 0.00 | Affected | 0.2139 | 0.5056 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1204C>A | L402M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402M is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain 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 likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact for this variant, 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 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -6.991 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.0 | 1.33 | Ambiguous | 0.73 | Ambiguous | 0.80 | Ambiguous | 0.071 | Likely Benign | -0.99 | Neutral | 0.994 | Probably Damaging | 0.938 | Probably Damaging | 3.73 | Benign | 0.02 | Affected | 0.1064 | 0.4095 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.224A>T | E75V 2D AIThe SynGAP1 missense variant E75V 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.443881 | Uncertain | 0.303 | 0.822 | 0.500 | -3.426 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.72 | Neutral | 0.789 | Possibly Damaging | 0.095 | Benign | 4.02 | Benign | 0.00 | Affected | 0.0878 | 0.7398 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2407A>C | K803Q 2D AIThe SynGAP1 missense variant K803Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -2.792 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -2.01 | Neutral | 0.984 | Probably Damaging | 0.773 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.4810 | 0.1398 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.2492A>G | E831G 2D AIThe SynGAP1 missense variant E831G is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, SIFT, FATHMM). The high‑accuracy AlphaMissense‑Optimized model predicts a benign effect, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. No Foldetta stability assessment is available. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any existing ClinVar annotation, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.617732 | Binding | 0.319 | 0.874 | 0.375 | -4.769 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -2.27 | Neutral | 0.625 | Possibly Damaging | 0.252 | Benign | 2.41 | Pathogenic | 0.04 | Affected | 0.2924 | 0.6205 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2933C>A | P978Q 2D AIThe SynGAP1 missense variant P978Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.975775 | Binding | 0.425 | 0.892 | 0.625 | -4.741 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.72 | Neutral | 0.990 | Probably Damaging | 0.726 | Possibly Damaging | 4.15 | Benign | 0.01 | Affected | 0.1651 | 0.5699 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3211G>T | G1071C 2D AIThe SynGAP1 missense variant G1071C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -5.364 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.182 | Likely Benign | -2.16 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 0.1323 | 0.4227 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.331C>A | P111T 2D AIThe SynGAP1 missense variant P111T 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 confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.800 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.44 | Neutral | 0.421 | Benign | 0.050 | Benign | 4.11 | Benign | 0.02 | Affected | 0.1650 | 0.5402 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3408G>C | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3408G>T | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is reported in gnomAD (variant ID 6-33443960‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443960-G-T | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3446C>A | P1149Q 2D AIThe SynGAP1 missense variant P1149Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -4.235 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -1.48 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.1515 | 0.4580 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3736A>G | K1246E 2D AIThe SynGAP1 missense variant K1246E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is 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 | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.052 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.80 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.89 | Benign | 1.00 | Tolerated | 0.3328 | 0.0514 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.872A>T | Y291F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce 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) is benign. Overall, the majority of evidence supports a benign classification, 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 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -4.095 | Likely Benign | 0.305 | Likely Benign | Likely Benign | -0.43 | Likely Benign | 0.1 | -0.10 | Likely Benign | -0.27 | Likely Benign | 0.71 | Ambiguous | 0.148 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.77 | Pathogenic | 0.27 | Tolerated | 0.2362 | 0.3441 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.914C>T | T305I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437819‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the balance of evidence from high‑confidence predictors leans toward a benign impact, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | Uncertain | 1 | 6-33437819-C-T | 1 | 6.20e-7 | -5.222 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.58 | Ambiguous | 0.48 | Likely Benign | 0.25 | Likely Benign | 0.224 | Likely Benign | -2.90 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | 3.40 | 20 | 0.0939 | 0.5693 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||
| c.2009T>A | L670Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, 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. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as Likely Benign, while Foldetta remains uncertain. Overall, the majority of available evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -8.217 | Likely Pathogenic | 0.306 | Likely Benign | Likely Benign | 1.02 | Ambiguous | 0.1 | 1.21 | Ambiguous | 1.12 | Ambiguous | 0.96 | Ambiguous | 0.152 | Likely Benign | -1.12 | Neutral | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.36 | Tolerated | 0.1088 | 0.1303 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2422G>C | V808L 2D AIThe SynGAP1 missense variant V808L 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 preponderance of evidence points to a benign impact for V808L, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.82 | Neutral | 0.911 | Possibly Damaging | 0.621 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1166 | 0.4745 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2422G>T | V808L 2D AIThe SynGAP1 missense variant V808L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.82 | Neutral | 0.911 | Possibly Damaging | 0.621 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1166 | 0.4745 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2679G>C | Q893H 2D AIThe SynGAP1 missense variant Q893H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q893H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.783 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.1708 | 0.3879 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2679G>T | Q893H 2D AIThe SynGAP1 missense variant Q893H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q893H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.783 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.1708 | 0.3879 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2975T>A | V992D 2D  AIThe SynGAP1 missense variant V992D 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 predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that V992D 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 | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -3.976 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.24 | Neutral | 0.302 | Benign | 0.158 | Benign | 4.21 | Benign | 0.05 | Affected | 0.1645 | 0.1056 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3207G>C | Q1069H 2D AIThe SynGAP1 missense variant Q1069H 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. 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.69 | Benign | 0.06 | Tolerated | 0.1560 | 0.4678 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3207G>T | Q1069H 2D AIThe SynGAP1 missense variant Q1069H 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. 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.69 | Benign | 0.06 | Tolerated | 0.1560 | 0.4678 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3683A>G | E1228G 2D AIThe SynGAP1 E1228G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show one benign call (AlphaMissense‑Optimized) and no decisive pathogenic evidence. Overall, the majority of standard tools (5 pathogenic vs 4 benign) indicate a pathogenic likelihood, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -6.273 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.249 | Likely Benign | -4.54 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.2598 | 0.4030 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3830A>G | H1277R 2D AIThe SynGAP1 missense variant H1277R 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), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. 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 votes). 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 there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -2.940 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -5.60 | Deleterious | 0.259 | Benign | 0.066 | Benign | 2.15 | Pathogenic | 0.00 | Affected | 0.1710 | 0.1562 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||||
| c.122G>C | R41P 2D AIThe SynGAP1 missense variant R41P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R41P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.311707 | Structured | 0.431757 | Uncertain | 0.344 | 0.765 | 0.375 | -3.863 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.70 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.2244 | 0.5735 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.199C>A | L67I 2D AIThe SynGAP1 missense variant L67I 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. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -4.387 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.29 | Neutral | 0.458 | Possibly Damaging | 0.364 | Benign | 4.10 | Benign | 0.00 | Affected | 0.0680 | 0.2919 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| 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.2692T>C | S898P 2D AIThe SynGAP1 missense variant S898P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.192 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.44 | Neutral | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.2400 | 0.6555 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3118G>A | G1040S 2D AIThe SynGAP1 missense variant G1040S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, SIFT, and FATHMM. 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 (six benign versus four pathogenic predictions) points to a benign impact for G1040S. 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 | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.179 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.653 | Likely Pathogenic | -1.81 | Neutral | 0.827 | Possibly Damaging | 0.375 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.2332 | 0.5298 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3316C>G | Q1106E 2D AIThe SynGAP1 missense variant Q1106E is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, PolyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q1106E, 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 | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -5.074 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -1.60 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.80 | Pathogenic | 0.15 | Tolerated | 0.1381 | 0.2663 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.331C>T | P111S 2D AIThe SynGAP1 missense variant P111S 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 also support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the collective predictions strongly suggest that P111S is most likely benign, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.773 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -1.03 | Neutral | 0.131 | Benign | 0.026 | Benign | 4.21 | Benign | 0.29 | Tolerated | 0.3515 | 0.4973 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.4022C>A | A1341E 2D AIThe SynGAP1 missense variant A1341E 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 the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta stability analysis is not available for this variant. Overall, the majority of 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 | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | -3.217 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.18 | Neutral | 0.012 | Benign | 0.015 | Benign | 4.05 | Benign | 0.01 | Affected | 0.1633 | 0.2624 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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.2149C>G | L717V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717V 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, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Two tools predict a damaging effect: polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Stability‑based methods (FoldX, Rosetta, Foldetta) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as inconclusive. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, 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 | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -6.164 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 1.53 | Ambiguous | 0.0 | 1.25 | Ambiguous | 1.39 | Ambiguous | 0.09 | Likely Benign | 0.119 | Likely Benign | -0.25 | Neutral | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.38 | Benign | 0.51 | Tolerated | 0.1226 | 0.2489 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2654C>G | P885R 2D AIThe SynGAP1 missense variant P885R is reported in gnomAD (ID 6‑33443206‑C‑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 further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact, 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 | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | 6-33443206-C-G | 1 | 6.20e-7 | -4.166 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.99 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.84 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1311 | 0.3505 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.2836G>A | G946R 2D AIThe SynGAP1 missense variant G946R 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b 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 outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | 0.1157 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2836G>C | G946R 2D AIThe SynGAP1 missense variant G946R 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b 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 outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | 0.1157 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3087G>C | Q1029H 2D AIThe SynGAP1 missense variant Q1029H 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, 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 classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.83 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.1268 | 0.4184 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3087G>T | Q1029H 2D AIThe SynGAP1 missense variant Q1029H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of the available predictions 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.83 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.1268 | 0.4184 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| 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.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.3154G>T | G1052W 2D AIThe SynGAP1 missense variant G1052W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -11.322 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.457 | Likely Benign | -0.90 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.0872 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.823C>A | P275T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P275T is reported in gnomAD (ID 6‑33437728‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore not considered evidence. No other tools provide conclusive results. Overall, the majority of predictions, including the SGM‑Consensus, indicate a pathogenic effect, 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 Pathogenic | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-A | 3 | 1.86e-6 | -8.708 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 0.3 | 1.15 | Ambiguous | 1.80 | Ambiguous | 0.69 | Ambiguous | 0.425 | Likely Benign | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0.1808 | 0.4000 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||
| c.1027G>C | V343L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only FATHMM predicts a pathogenic outcome, while FoldX and Rosetta provide uncertain results and are therefore not considered decisive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -6.268 | Likely Benign | 0.310 | Likely Benign | Likely Benign | -0.93 | Ambiguous | 0.2 | 0.66 | Ambiguous | -0.14 | Likely Benign | 0.16 | Likely Benign | 0.033 | Likely Benign | -1.09 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.12 | Pathogenic | 0.64 | Tolerated | 0.1361 | 0.5008 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1246C>G | L416V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and ESM1b. 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 uncertain. Overall, the majority of evidence points to a benign impact for the variant. This conclusion is not contradicted by any ClinVar annotation, as the variant is not present in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -7.861 | In-Between | 0.310 | Likely Benign | Likely Benign | 1.46 | Ambiguous | 0.0 | 1.78 | Ambiguous | 1.62 | Ambiguous | 0.45 | Likely Benign | 0.124 | Likely Benign | -1.47 | Neutral | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.42 | Benign | 0.53 | Tolerated | 0.1563 | 0.3550 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1346G>T | S449I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. Rosetta and Foldetta give uncertain results. 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 also remains uncertain. Overall, the majority of evidence (7 benign vs. 3 pathogenic) 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 | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -9.549 | Likely Pathogenic | 0.310 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.1 | -1.39 | Ambiguous | -0.68 | Ambiguous | 0.13 | Likely Benign | 0.105 | Likely Benign | -3.23 | Deleterious | 0.559 | Possibly Damaging | 0.044 | Benign | 3.40 | Benign | 0.14 | Tolerated | 0.0756 | 0.5006 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| c.2342T>C | M781T 2D AIThe SynGAP1 missense variant M781T is catalogued in gnomAD (ID 6‑33442894‑T‑C) and has no ClinVar entry. Across the evaluated in‑silico tools, every predictor classifies 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 reports a pathogenic or likely pathogenic outcome. The high‑accuracy consensus methods reinforce this view: 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 predictor, has no available result for this variant. Based on the unanimous benign predictions and the lack of any ClinVar pathogenic annotation, 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 | 6-33442894-T-C | 1 | 6.21e-7 | -3.774 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -0.86 | Neutral | 0.015 | Benign | 0.037 | Benign | 2.75 | Benign | 0.59 | Tolerated | 3.64 | 6 | 0.2267 | 0.1599 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.2356C>G | L786V 2D AIThe SynGAP1 missense variant L786V is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). 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 as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently has no classification for L786V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | -4.607 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.00 | Pathogenic | 0.00 | Affected | 0.1683 | 0.4049 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2446T>G | S816A 2D AIThe SynGAP1 missense variant S816A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -4.543 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.07 | Neutral | 0.953 | Possibly Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.59 | Tolerated | 0.5307 | 0.4532 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2668C>G | R890G 2D AIThe SynGAP1 missense variant R890G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that R890G 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 | 0.531156 | Binding | 0.284 | 0.928 | 0.625 | -2.080 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -1.99 | Neutral | 0.990 | Probably Damaging | 0.894 | Possibly Damaging | 3.97 | Benign | 0.33 | Tolerated | 0.3734 | 0.2711 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3705G>A | M1235I 2D AIThe SynGAP1 missense variant M1235I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic effect. 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 “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | Uncertain | 1 | -4.312 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.44 | Neutral | 0.139 | Benign | 0.056 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1224 | 0.2691 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.3705G>C | M1235I 2D AIThe SynGAP1 missense variant M1235I is reported in gnomAD (6-33446697‑G‑C) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | 6-33446697-G-C | 1 | 6.20e-7 | -4.312 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.44 | Neutral | 0.139 | Benign | 0.056 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1224 | 0.2691 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
| c.3705G>T | M1235I 2D AIThe SynGAP1 missense variant M1235I is not reported in ClinVar and is absent from gnomAD. 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 preponderance of evidence supports a benign classification for M1235I, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -4.312 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.44 | Neutral | 0.139 | Benign | 0.056 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1224 | 0.2691 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.4024G>C | D1342H 2D  AIThe SynGAP1 missense variant D1342H 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of available predictions indicates that D1342H 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 | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | -3.765 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.56 | Neutral | 0.834 | Possibly Damaging | 0.400 | Benign | 4.00 | Benign | 0.02 | Affected | 0.2365 | 0.6177 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.9G>C | R3S 2D AIThe SynGAP1 missense variant R3S 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 from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -2.296 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -0.53 | Neutral | 0.115 | Benign | 0.013 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3148 | 0.4732 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.9G>T | R3S 2D AIThe SynGAP1 missense variant R3S is reported in gnomAD (ID 6‑33420273‑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 it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign effect. 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 | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | 6-33420273-G-T | 1 | 6.50e-7 | -2.296 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -0.53 | Neutral | 0.115 | Benign | 0.013 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3148 | 0.4732 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||
| c.2246G>C | R749P 2D AIThe SynGAP1 missense variant R749P 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 R749P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -2.467 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.2195 | 0.4878 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2724G>C | Q908H 2D AIThe SynGAP1 missense variant Q908H is listed in ClinVar (ID 436926.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443276‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | Conflicting | 4 | 6-33443276-G-C | 1 | 6.20e-7 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1293 | 0.3597 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||
| c.2724G>T | Q908H 2D AIThe SynGAP1 missense variant Q908H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q908H, 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 | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1293 | 0.3597 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.2762T>A | L921Q 2D AIThe SynGAP1 missense variant L921Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, 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 | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -2.389 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -0.62 | Neutral | 0.994 | Probably Damaging | 0.940 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 0.1097 | 0.1119 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3152G>A | G1051D 2D AISynGAP1 missense variant G1051D is listed in ClinVar as Benign and is present in gnomAD (variant ID 6‑33443704‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Benign | 1 | 6-33443704-G-A | 2 | 1.24e-6 | -9.379 | Likely Pathogenic | 0.311 | Likely Benign | Likely Benign | 0.445 | Likely Benign | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | 0.1872 | 0.2235 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||
| c.3737A>T | K1246M 2D  AIThe SynGAP1 missense variant K1246M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a benign likelihood; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for K1246M, 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 | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -3.663 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.961 | Probably Damaging | 2.60 | Benign | 0.01 | Affected | 0.0938 | 0.2598 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3869G>C | R1290T 2D AIThe SynGAP1 missense variant R1290T 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, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, 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 unavailable. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.044 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -3.50 | Deleterious | 0.625 | Possibly Damaging | 0.266 | Benign | 2.64 | Benign | 0.01 | Affected | 0.1607 | 0.3359 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| 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.2630T>C | L877P 2D AIThe SynGAP1 missense variant L877P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, 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 | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -4.960 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.57 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.3899 | 0.1543 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3175G>T | G1059W 2D AIThe SynGAP1 missense variant G1059W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -11.549 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.0925 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3712C>G | Q1238E 2D AIThe SynGAP1 missense variant Q1238E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized predicting benign, while SGM Consensus and Foldetta are unavailable. Overall, the majority of standard predictors (5 pathogenic vs 4 benign) lean toward a pathogenic interpretation, and this assessment does not contradict ClinVar status because no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | -10.421 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -1.90 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.37 | Pathogenic | 0.02 | Affected | 0.1078 | 0.1921 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.823C>T | P275S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑T). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, 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 evidence points to a pathogenic impact for P275S, 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. | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-T | 1 | 6.20e-7 | -7.886 | In-Between | 0.312 | Likely Benign | Likely Benign | 2.11 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.70 | Ambiguous | 0.77 | Ambiguous | 0.388 | Likely Benign | -5.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.78 | Pathogenic | 0.03 | Affected | 3.38 | 19 | 0.3489 | 0.3339 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.2261A>G | E754G 2D AIThe SynGAP1 missense variant E754G 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv 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 | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -5.029 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.52 | Neutral | 0.801 | Possibly Damaging | 0.339 | Benign | 2.94 | Benign | 0.13 | Tolerated | 0.2631 | 0.5820 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2509G>C | V837L 2D AIThe SynGAP1 missense variant V837L 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, 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 not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -4.895 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.15 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.17 | Tolerated | 0.1039 | 0.4623 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3106C>G | Q1036E 2D AIThe SynGAP1 missense variant Q1036E 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains nine tools, while the pathogenic group contains one (SIFT). 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) reports “Likely Benign.” Foldetta results are unavailable, so they do not influence the assessment. Overall, the evidence strongly suggests 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 | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.797 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.22 | Neutral | 0.264 | Benign | 0.062 | Benign | 2.59 | Benign | 0.03 | Affected | 0.1629 | 0.3484 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.113C>G | P38R 2D AIThe SynGAP1 missense variant P38R 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 P38R, 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 | 0.497853 | Structured | 0.433285 | Uncertain | 0.344 | 0.791 | 0.375 | -1.799 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.168 | Likely Benign | -2.29 | Neutral | 0.989 | Probably Damaging | 0.975 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 0.1620 | 0.4060 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| 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.2260G>C | E754Q 2D AIThe SynGAP1 missense variant E754Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as 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 preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -5.324 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.76 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.48 | Pathogenic | 0.27 | Tolerated | 0.1112 | 0.6714 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2741A>G | D914G 2D AIThe SynGAP1 missense variant D914G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for D914G, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -1.486 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.46 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.4421 | 0.7257 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2969C>A | S990Y 2D AIThe SynGAP1 missense variant S990Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. The predictions do not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.272 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -2.52 | Deleterious | 0.832 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 0.0893 | 0.5832 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.727A>G | I243V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243V 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, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. 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 Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -8.237 | Likely Pathogenic | 0.314 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.64 | Ambiguous | 0.39 | Likely Benign | 0.445 | Likely Benign | -0.39 | Neutral | 0.617 | Possibly Damaging | 0.140 | Benign | 5.71 | Benign | 0.15 | Tolerated | 0.1019 | 0.2591 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.890A>G | K297R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297R 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, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, and ESM1b. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign; and Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts benign. Based on the aggregate of these predictions, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -7.877 | In-Between | 0.314 | Likely Benign | Likely Benign | -0.86 | Ambiguous | 0.3 | 0.67 | Ambiguous | -0.10 | Likely Benign | 0.66 | Ambiguous | 0.257 | Likely Benign | -2.36 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.66 | Pathogenic | 0.19 | Tolerated | 0.4828 | 0.1506 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.100T>C | Y34H 2D AIThe SynGAP1 missense variant Y34H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Y34H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -2.929 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.53 | Neutral | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.2630 | 0.1062 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2237T>A | V746E 2D  AIThe SynGAP1 missense variant V746E 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 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. No Foldetta stability data are 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -4.136 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.94 | Neutral | 0.642 | Possibly Damaging | 0.316 | Benign | 2.85 | Benign | 0.05 | Affected | 0.0928 | 0.1813 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>G | V837G 2D AIThe SynGAP1 missense variant V837G 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 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 | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -2.599 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.187 | Likely Benign | 0.93 | Neutral | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 1.00 | Tolerated | 0.2260 | 0.2422 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2554G>C | G852R 2D AIThe SynGAP1 missense variant G852R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G852R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -5.507 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.31 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.16 | Benign | 0.01 | Affected | 0.0978 | 0.4446 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2842G>C | G948R 2D AIThe SynGAP1 missense variant G948R 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, reports a “Likely Benign” classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -6.782 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.266 | Likely Benign | -0.60 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.58 | Benign | 0.04 | Affected | 0.1069 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3184G>T | G1062W 2D AIThe SynGAP1 missense variant G1062W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which labels the variant as “Likely Benign.” Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b, all of which classify the change as damaging. 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. 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 lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -9.667 | Likely Pathogenic | 0.315 | Likely Benign | Likely Benign | 0.401 | Likely Benign | -1.38 | Neutral | 0.993 | Probably Damaging | 0.890 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.0908 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3947A>C | N1316T 2D AIThe SynGAP1 missense variant N1316T is reported in gnomAD (ID 6‑33451821‑A‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. When predictions are grouped by consensus, the benign‑predicating tools outnumber the pathogenic ones. 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.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion 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 | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451821-A-C | -3.080 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -3.18 | Deleterious | 0.127 | Benign | 0.045 | Benign | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1450 | 0.6621 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||||
| 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.2608C>A | L870M 2D AIThe SynGAP1 missense variant L870M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.809 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.01 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.10 | Tolerated | 0.0757 | 0.3956 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2905G>A | G969R 2D AIThe SynGAP1 missense variant G969R 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 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 annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | 0.1039 | 0.5473 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2905G>C | G969R 2D AIThe SynGAP1 missense variant G969R 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 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 annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | 0.1039 | 0.5473 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.667A>G | T223A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223A is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33435518‑A‑G). Functional prediction tools that agree on a benign effect include FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and PROVEAN. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | 0.574 | Likely Pathogenic | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 0.2982 | 0.3031 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.710C>G | A237G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the balance of evidence, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -6.647 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 1.00 | Ambiguous | 0.0 | 2.01 | Destabilizing | 1.51 | Ambiguous | 1.14 | Destabilizing | 0.538 | Likely Pathogenic | -2.91 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.81 | Benign | 0.05 | Affected | 0.1809 | 0.2910 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.11C>T | S4F 2D AIThe SynGAP1 missense variant S4F 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. Overall, the majority of evidence points to a benign impact for S4F, and this conclusion 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.880 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.17 | Neutral | 0.676 | Possibly Damaging | 0.485 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.0686 | 0.6270 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.1492A>G | M498V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M498V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, FATHMM). Rosetta is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta predicts a pathogenic effect on protein stability. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -3.229 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 2.74 | Destabilizing | 0.1 | 1.26 | Ambiguous | 2.00 | Destabilizing | 1.17 | Destabilizing | 0.483 | Likely Benign | -1.82 | Neutral | 0.752 | Possibly Damaging | 0.279 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.2737 | 0.2737 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.2083C>G | L695V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta is also unavailable. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -10.605 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 1.61 | Ambiguous | 0.0 | 1.57 | Ambiguous | 1.59 | Ambiguous | 1.19 | Destabilizing | 0.274 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.694 | Possibly Damaging | 3.20 | Benign | 0.02 | Affected | 0.1158 | 0.2828 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.3163G>T | G1055W 2D AIThe SynGAP1 missense variant G1055W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -11.436 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 0.367 | Likely Benign | -0.77 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0899 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.4013G>A | R1338Q 2D AIThe SynGAP1 missense variant R1338Q is listed in ClinVar (ID 450879.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451887‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports it as “Likely Benign.” In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.977425 | Binding | 0.393 | 0.697 | 1.000 | Conflicting | 3 | 6-33451887-G-A | 12 | 8.40e-6 | -3.494 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.87 | Neutral | 0.896 | Possibly Damaging | 0.194 | Benign | 3.81 | Benign | 0.02 | Affected | 3.77 | 5 | 0.3528 | 0.2905 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.4025A>T | D1342V 2D  AIThe SynGAP1 missense variant D1342V 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign and the SGM‑Consensus also indicating a likely benign outcome; the Foldetta protein‑folding stability analysis is 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 | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | -2.890 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.27 | Neutral | 0.588 | Possibly Damaging | 0.212 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1214 | 0.5617 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.185A>C | D62A 2D  AIThe SynGAP1 D62A 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 unavailable. Based on the preponderance of 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 | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -3.983 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.67 | Neutral | 0.006 | Benign | 0.023 | Benign | 4.09 | Benign | 0.00 | Affected | 0.4152 | 0.5972 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| 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.217A>T | R73W 2D AIThe SynGAP1 missense variant R73W 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, 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 | 0.501700 | Disordered | 0.453164 | Uncertain | 0.332 | 0.826 | 0.375 | -5.874 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -1.96 | Neutral | 0.962 | Probably Damaging | 0.274 | Benign | 3.98 | Benign | 0.00 | Affected | 0.1505 | 0.4035 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2543G>A | G848D 2D AIThe SynGAP1 missense variant G848D 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 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 | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -0.059 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 2.94 | Neutral | 0.008 | Benign | 0.019 | Benign | 2.95 | Benign | 0.81 | Tolerated | 0.1702 | 0.1392 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2848G>C | G950R 2D AIThe SynGAP1 missense variant G950R 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, 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 preponderance of evidence points to a benign impact for G950R, 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 | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.929 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.388 | Likely Benign | -1.10 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.26 | Pathogenic | 0.01 | Affected | 0.1009 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>T | P1146S 2D AIThe SynGAP1 missense variant P1146S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33444471-C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | 6-33444471-C-T | 2 | 1.24e-6 | -3.045 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.470 | Likely Benign | -3.66 | Deleterious | 0.945 | Possibly Damaging | 0.760 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3408 | 0.5186 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3446C>T | P1149L 2D AIThe SynGAP1 missense variant P1149L 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 classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. 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 points to a benign effect for P1149L, 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 | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -3.438 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -1.90 | Neutral | 0.818 | Possibly Damaging | 0.381 | Benign | 2.67 | Benign | 0.01 | Affected | 0.2235 | 0.5918 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>A | T1310K 2D AIThe SynGAP1 missense variant T1310K 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. 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 | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -4.388 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.64 | Neutral | 0.111 | Benign | 0.116 | Benign | 2.80 | Benign | 0.04 | Affected | 0.0992 | 0.2978 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.88C>G | H30D 2D AIThe SynGAP1 missense variant H30D 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 H30D, 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 | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -2.838 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.150 | Likely Benign | -2.25 | Neutral | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.3048 | 0.3296 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.1075A>C | T359P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, 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 FoldX, 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. 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 | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | -6.884 | Likely Benign | 0.319 | Likely Benign | Likely Benign | 0.97 | Ambiguous | 0.1 | 1.27 | Ambiguous | 1.12 | Ambiguous | 0.68 | Ambiguous | 0.248 | Likely Benign | -2.36 | Neutral | 0.627 | Possibly Damaging | 0.091 | Benign | 1.78 | Pathogenic | 0.14 | Tolerated | 0.2352 | 0.5611 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.2546A>T | D849V 2D AIThe SynGAP1 missense variant D849V 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 interpretation: 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 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 | 0.712013 | Disordered | 0.554191 | Binding | 0.319 | 0.813 | 0.500 | -3.819 | Likely Benign | 0.319 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -2.10 | Neutral | 0.918 | Possibly Damaging | 0.481 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.1161 | 0.7963 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2990C>A | A997D 2D AIThe SynGAP1 missense variant A997D 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 for this variant. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic annotation. 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 | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -5.251 | Likely Benign | 0.319 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -1.09 | Neutral | 0.411 | Benign | 0.120 | Benign | 4.15 | Benign | 0.00 | Affected | 0.1815 | 0.2143 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.572G>C | S191T 2D AIThe SynGAP1 missense variant S191T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of evidence supports a benign classification, 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. | Likely Benign | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.315 | In-Between | 0.319 | Likely Benign | Likely Benign | 0.150 | Likely Benign | -2.34 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.81 | Benign | 0.03 | Affected | 0.1466 | 0.7405 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2540A>C | Q847P 2D AIThe SynGAP1 missense variant Q847P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑vs‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (AlphaMissense‑Optimized and AlphaMissense‑Default) indicate a benign outcome, while the consensus of other tools is mixed. Thus, the variant is most likely benign based on current 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. | 0.653063 | Disordered | 0.577677 | Binding | 0.282 | 0.818 | 0.500 | -6.742 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.331 | Likely Benign | -3.83 | Deleterious | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.2290 | 0.4831 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2672T>A | L891H 2D AIThe SynGAP1 missense variant L891H 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 the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of 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 | 0.712013 | Disordered | 0.505861 | Binding | 0.305 | 0.923 | 0.750 | -4.604 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.79 | Neutral | 0.122 | Benign | 0.134 | Benign | 2.69 | Benign | 0.00 | Affected | 0.1099 | 0.1189 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3002T>G | L1001R 2D AIThe SynGAP1 missense variant L1001R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -2.285 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.09 | Neutral | 0.966 | Probably Damaging | 0.708 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1299 | 0.0832 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3226T>A | L1076M 2D AIThe SynGAP1 missense variant L1076M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, 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 | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -5.047 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 0.02 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0.0886 | 0.4147 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.380G>A | R127Q 2D AIThe SynGAP1 missense variant R127Q (ClinVar ID 2898917.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33432245‑G‑A). 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, 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 stability analysis is unavailable. 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 | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | Uncertain | 1 | 6-33432245-G-A | 6 | 3.72e-6 | -1.711 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.04 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.04 | Benign | 0.02 | Affected | 3.74 | 4 | 0.3018 | 0.2852 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.70G>C | V24L 2D AIThe SynGAP1 missense variant V24L 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 likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1102 | 0.5226 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.70G>T | V24L 2D AIThe SynGAP1 missense variant V24L 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 likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1102 | 0.5226 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.996C>A | D332E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332E 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, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome 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 because it yields a 2‑to‑2 split. Overall, the majority of evidence points to a benign effect. 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. | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -4.915 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.04 | Likely Benign | 0.27 | Likely Benign | 0.35 | Likely Benign | 0.191 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.29 | Pathogenic | 0.24 | Tolerated | 0.0970 | 0.3915 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.996C>G | D332E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332E 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect 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‑to‑2 split. Overall, the majority of evidence supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -4.915 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.04 | Likely Benign | 0.27 | Likely Benign | 0.35 | Likely Benign | 0.188 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.29 | Pathogenic | 0.24 | Tolerated | 0.0970 | 0.3915 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.104T>A | V35D 2D AIThe SynGAP1 missense variant V35D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Overall, the majority of evidence points to the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | -4.232 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -0.42 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.1540 | 0.1547 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.1055C>T | T352I 2D AISynGAP1 T352I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. With seven benign versus five pathogenic predictions and two high‑accuracy benign versus one pathogenic, the evidence leans toward a benign effect. This conclusion does not contradict 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 Pathogenic | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -8.023 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | -0.54 | Ambiguous | 0.7 | 0.43 | Likely Benign | -0.06 | Likely Benign | 0.09 | Likely Benign | 0.099 | Likely Benign | -3.02 | Deleterious | 0.627 | Possibly Damaging | 0.196 | Benign | 1.67 | Pathogenic | 0.14 | Tolerated | 0.1009 | 0.6484 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.365C>A | P122H 2D AIThe SynGAP1 missense variant P122H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for P122H. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -4.993 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -1.82 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2306 | 0.4213 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.568A>G | S190G 2D AIThe SynGAP1 missense variant S190G 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 reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability predictor, 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 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 | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -5.440 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.26 | Neutral | 0.243 | Benign | 0.079 | Benign | 4.11 | Benign | 0.19 | Tolerated | 0.2780 | 0.4765 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.905C>T | S302F 2D AIThe SynGAP1 missense variant S302F 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b; Rosetta’s output is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence supports a benign impact for S302F, 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 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.483 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.5 | 0.71 | Ambiguous | 0.34 | Likely Benign | -0.21 | Likely Benign | 0.073 | Likely Benign | -0.92 | Neutral | 0.570 | Possibly Damaging | 0.383 | Benign | 4.06 | Benign | 0.01 | Affected | 0.0705 | 0.6092 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| 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.2509G>T | V837F 2D  AIThe SynGAP1 missense variant V837F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -5.223 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -1.41 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.08 | Tolerated | 0.0749 | 0.3744 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3205C>G | Q1069E 2D AIThe SynGAP1 missense variant Q1069E 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 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -5.165 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -0.68 | Neutral | 0.451 | Benign | 0.266 | Benign | 2.76 | Benign | 0.33 | Tolerated | 0.1460 | 0.3127 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3781A>T | S1261C 2D AIThe SynGAP1 missense variant S1261C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the variant as damaging. The SGM‑Consensus, which aggregates these predictions, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains benign, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -8.275 | Likely Pathogenic | 0.322 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -3.51 | Deleterious | 0.999 | Probably Damaging | 0.947 | Probably Damaging | 2.20 | Pathogenic | 0.04 | Affected | 0.0760 | 0.4580 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.64A>G | R22G 2D AIThe SynGAP1 missense variant R22G is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33420328‑A‑G). 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 further support a benign outcome: 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 impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420328-A-G | -3.628 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.185 | Likely Benign | -0.42 | Neutral | 0.462 | Possibly Damaging | 0.152 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3590 | 0.4098 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| 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.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.2584A>G | N862D 2D AIThe SynGAP1 missense variant N862D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -5.255 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -1.22 | Neutral | 0.995 | Probably Damaging | 0.926 | Probably Damaging | 4.06 | Benign | 0.51 | Tolerated | 0.1786 | 0.4764 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3178G>C | G1060R 2D AIThe SynGAP1 missense variant G1060R 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (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 G1060R, 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 | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -8.225 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 0.362 | Likely Benign | -0.29 | Neutral | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.63 | Benign | 0.17 | Tolerated | 0.1038 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3251C>A | P1084H 2D AIThe SynGAP1 missense variant P1084H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443803‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which reports “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Thus, the variant is most likely benign, and its prediction profile does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | Uncertain | 1 | 6-33443803-C-A | 1 | 6.31e-7 | -4.125 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -3.16 | Deleterious | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1751 | 0.5523 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.2105A>C | Q702P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, more tools predict pathogenicity (7) than benignity (5), and the high‑accuracy pathogenic prediction from Foldetta further supports this. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -10.361 | Likely Pathogenic | 0.324 | Likely Benign | Likely Benign | 1.76 | Ambiguous | 0.1 | 7.05 | Destabilizing | 4.41 | Destabilizing | -0.04 | Likely Benign | 0.369 | Likely Benign | -4.71 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.42 | Benign | 0.05 | Affected | 0.1877 | 0.3371 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||
| c.3830A>C | H1277P 2D AIThe SynGAP1 missense variant H1277P is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447878‑A‑C). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | 6-33447878-A-C | -3.829 | Likely Benign | 0.324 | Likely Benign | Likely Benign | 0.237 | Likely Benign | -7.14 | Deleterious | 0.586 | Possibly Damaging | 0.287 | Benign | 2.12 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2266 | 0.3393 | -2 | 0 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||
| c.160A>G | N54D 2D AIThe SynGAP1 missense variant N54D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is labeled “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 (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -6.980 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.75 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.22 | Benign | 0.00 | Affected | 0.1826 | 0.4496 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.295G>C | E99Q 2D AIThe SynGAP1 missense variant E99Q is reported in gnomAD (6-33425903‑G‑C) 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 preponderance of evidence points to a benign impact for E99Q, 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 | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | 6-33425903-G-C | 1 | 6.20e-7 | -3.675 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.82 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1672 | 0.7727 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.3512C>T | A1171V 2D AIThe SynGAP1 missense variant A1171V 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 indicate a benign effect, and no tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.516 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.72 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.34 | Benign | 0.11 | Tolerated | 0.1019 | 0.4611 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| c.3611C>T | S1204L 2D AIThe SynGAP1 missense variant S1204L is reported in gnomAD (variant ID 6‑33446603‑C‑T) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta results are not available. 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 | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | 6-33446603-C-T | 1 | 6.20e-7 | -4.672 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.375 | Likely Benign | -0.86 | Neutral | 0.035 | Benign | 0.028 | Benign | 5.35 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1000 | 0.4082 | -2 | -3 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||
| c.3778A>C | K1260Q 2D AIThe SynGAP1 missense variant K1260Q is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33446770‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. ESM1b is uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict, and Foldetta results are unavailable. Overall, the majority of evidence points to pathogenicity, and this conclusion does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | 6-33446770-A-C | -7.830 | In-Between | 0.325 | Likely Benign | Likely Benign | 0.367 | Likely Benign | -3.06 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3597 | 0.1102 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||
| c.3831C>A | H1277Q 2D  AIThe SynGAP1 missense variant H1277Q is reported in gnomAD (ID 6‑33447879‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b; pathogenic predictions come from PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta data are unavailable. Overall, the majority of evidence points toward a benign effect, and this conclusion does not conflict with 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. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | 6-33447879-C-A | -3.323 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -5.34 | Deleterious | 0.004 | Benign | 0.010 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1311 | 0.2351 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.3831C>G | H1277Q 2D AIThe SynGAP1 missense variant H1277Q is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b; pathogenic predictions come from PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic). Foldetta results are not available. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). 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. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -3.323 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -5.34 | Deleterious | 0.004 | Benign | 0.010 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1311 | 0.2351 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.2297C>G | S766C 2D AIThe SynGAP1 missense variant S766C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S766C, 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -7.681 | In-Between | 0.326 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -2.02 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.1049 | 0.6110 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3044C>T | T1015I 2D AIThe SynGAP1 missense variant T1015I is not reported in ClinVar and has no entry in 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for T1015I, 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -4.713 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.06 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.53 | Benign | 0.07 | Tolerated | 0.1232 | 0.4871 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3160G>C | G1054R 2D AIThe SynGAP1 missense variant G1054R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G1054R, 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 | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -8.863 | Likely Pathogenic | 0.326 | Likely Benign | Likely Benign | 0.234 | Likely Benign | 0.29 | Neutral | 0.988 | Probably Damaging | 0.589 | Possibly Damaging | 4.05 | Benign | 0.42 | Tolerated | 0.1164 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3209G>A | R1070K 2D AIThe SynGAP1 missense variant R1070K is listed in ClinVar with an “Uncertain” status and is not reported in 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 return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta results are unavailable. Based on the unanimous benign 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 | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | Conflicting | 2 | -5.093 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.049 | Benign | 0.048 | Benign | 3.86 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.4997 | 0.4867 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||
| c.3716C>A | A1239D 2D AIThe SynGAP1 missense variant A1239D 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), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. 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 votes). Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic predictions) supports a benign classification. 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. | Coiled-coil | 0.541878 | Disordered | 0.534779 | Binding | 0.887 | 0.542 | 0.250 | -6.177 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.60 | Deleterious | 0.270 | Benign | 0.136 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.1521 | 0.2062 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3475T>G | S1159A 2D AIThe SynGAP1 missense variant S1159A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -3.653 | Likely Benign | 0.327 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.46 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.71 | Benign | 0.44 | Tolerated | 0.4754 | 0.4541 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.1279C>T | H427Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H427Y 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, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly indicate a benign effect. 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 reported). 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 | -6.824 | Likely Benign | 0.328 | Likely Benign | Likely Benign | -0.08 | Likely Benign | 0.0 | -0.37 | Likely Benign | -0.23 | Likely Benign | 0.18 | Likely Benign | 0.180 | Likely Benign | -3.47 | Deleterious | 0.815 | Possibly Damaging | 0.073 | Benign | 3.44 | Benign | 0.01 | Affected | 0.0958 | 0.4029 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.3167G>A | G1056D 2D AIThe SynGAP1 missense variant G1056D 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic) supports a benign classification. 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. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -10.352 | Likely Pathogenic | 0.328 | Likely Benign | Likely Benign | 0.380 | Likely Benign | 0.09 | Neutral | 0.666 | Possibly Damaging | 0.193 | Benign | 1.83 | Pathogenic | 0.92 | Tolerated | 0.1912 | 0.2626 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3271C>G | L1091V 2D AIThe SynGAP1 missense variant L1091V 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, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -4.587 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.62 | Neutral | 0.779 | Possibly Damaging | 0.211 | Benign | 2.57 | Benign | 0.08 | Tolerated | 0.1560 | 0.3561 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3311C>G | P1104R 2D AIThe SynGAP1 missense variant P1104R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.864 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.64 | Neutral | 0.986 | Probably Damaging | 0.761 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 0.1387 | 0.3703 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3674C>T | S1225F 2D AIThe SynGAP1 missense variant S1225F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1225F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -7.938 | In-Between | 0.328 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.34 | Neutral | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 5.37 | Benign | 0.06 | Tolerated | 0.0505 | 0.4979 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||
| c.3878A>T | D1293V 2D AIThe SynGAP1 missense variant D1293V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of available predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -3.817 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.343 | Likely Benign | -6.03 | Deleterious | 0.960 | Probably Damaging | 0.679 | Possibly Damaging | 2.16 | Pathogenic | 0.00 | Affected | 0.0896 | 0.3603 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.596A>T | N199I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199I 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), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.299 | Likely Pathogenic | 0.328 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.08 | Likely Benign | 0.20 | Likely Benign | 0.066 | Likely Benign | -3.27 | Deleterious | 0.316 | Benign | 0.045 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0450 | 0.6009 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||
| 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.2917G>A | G973R 2D AIThe SynGAP1 missense variant G973R is not reported in ClinVar and is absent from gnomAD. 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 as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. 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 | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>C | G973R 2D AIThe SynGAP1 missense variant G973R is not reported in ClinVar and is absent from gnomAD. 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 call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>T | G973W 2D AIThe SynGAP1 missense variant G973W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G973W, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -6.896 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0846 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>A | G1303D 2D AIThe SynGAP1 missense variant G1303D is not reported in ClinVar and is absent from gnomAD, indicating no known population 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. 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.825 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 2.64 | Neutral | 0.002 | Benign | 0.008 | Benign | 3.22 | Benign | 1.00 | Tolerated | 0.1784 | 0.1452 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1604G>T | S535I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the preponderance of evidence points to a benign impact for S535I, 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 | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -8.073 | Likely Pathogenic | 0.330 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | -0.42 | Likely Benign | 0.04 | Likely Benign | 0.14 | Likely Benign | 0.246 | Likely Benign | -2.49 | Neutral | 0.004 | Benign | 0.004 | Benign | -1.25 | Pathogenic | 0.07 | Tolerated | 0.1123 | 0.5571 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| c.1986G>C | Q662H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662H is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate 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, 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” status. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote) predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. FoldX alone is uncertain, but this does not alter the overall consensus. Based on the collective predictions, 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 | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -6.357 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.36 | Likely Benign | -0.11 | Likely Benign | 0.159 | Likely Benign | -2.00 | Neutral | 0.891 | Possibly Damaging | 0.243 | Benign | 3.42 | Benign | 0.15 | Tolerated | 0.1674 | 0.3186 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1986G>T | Q662H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662H is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution 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” status, and FoldX is inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is 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 annotation (none is 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 | -6.357 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.36 | Likely Benign | -0.11 | Likely Benign | 0.159 | Likely Benign | -2.00 | Neutral | 0.891 | Possibly Damaging | 0.243 | Benign | 3.42 | Benign | 0.15 | Tolerated | 0.1674 | 0.3186 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| 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.2728G>A | G910S 2D AIThe SynGAP1 missense variant G910S 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 a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -3.195 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.79 | Benign | 0.06 | Tolerated | 0.2671 | 0.4492 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>A | G1048E 2D AIThe SynGAP1 missense variant G1048E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only REVEL predicts a pathogenic outcome, while ESM1b is uncertain. 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. 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 | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -7.028 | In-Between | 0.331 | Likely Benign | Likely Benign | 0.529 | Likely Pathogenic | -0.62 | Neutral | 0.018 | Benign | 0.030 | Benign | 2.54 | Benign | 0.10 | Tolerated | 0.1444 | 0.4063 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.1447A>C | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. 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 | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | 0.341 | Likely Benign | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 0.0664 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1447A>T | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. 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 | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | 0.342 | Likely Benign | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 0.0664 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1936C>G | L646V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM, whereas pathogenic predictions arise from FoldX, Rosetta, premPS, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs 1 pathogenic votes). High‑accuracy assessments further indicate AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign 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 | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -8.995 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 3.82 | Destabilizing | 0.2 | 2.01 | Destabilizing | 2.92 | Destabilizing | 1.41 | Destabilizing | 0.125 | Likely Benign | -1.40 | Neutral | 0.040 | Benign | 0.021 | Benign | 3.21 | Benign | 0.03 | Affected | 0.2200 | 0.3767 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2501T>C | M834T 2D AIThe SynGAP1 missense variant M834T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for M834T, 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 | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.525 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -2.03 | Neutral | 0.224 | Benign | 0.085 | Benign | 2.45 | Pathogenic | 0.00 | Affected | 0.1757 | 0.1799 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2650C>T | R884W 2D AIThe SynGAP1 missense variant R884W is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443202‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta (protein‑folding stability) result is available for this variant. Overall, the majority of computational predictions, including the high‑accuracy tools, indicate that R884W is most likely benign, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | Uncertain | 1 | 6-33443202-C-T | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.151 | Likely Benign | 0.26 | Neutral | 0.995 | Probably Damaging | 0.812 | Possibly Damaging | 2.56 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1223 | 0.3304 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2798A>C | H933P 2D AIThe SynGAP1 missense variant H933P 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 ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, six tools predict pathogenicity versus three predicting benign, and the high‑accuracy benign prediction is outweighed by the majority of pathogenic calls. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -3.890 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.508 | Likely Pathogenic | -5.39 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.36 | Pathogenic | 0.02 | Affected | 0.1821 | 0.4400 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2902G>C | G968R 2D AIThe SynGAP1 missense variant G968R 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 from 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 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 | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -4.492 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -0.63 | Neutral | 0.005 | Benign | 0.012 | Benign | 4.19 | Benign | 0.08 | Tolerated | 0.0972 | 0.5017 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.41C>T | P14L 2D AIThe SynGAP1 missense variant P14L is catalogued in gnomAD (ID 6‑33420305‑C‑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 report benign or tolerated outcomes, while the single pathogenic call comes from 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise favors benign; Foldetta results are unavailable. Overall, the consensus of available predictions points to a benign impact for P14L, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | 6-33420305-C-T | -3.277 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.53 | Neutral | 0.062 | Benign | 0.004 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2618 | 0.7197 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.115T>G | Y39D 2D  AIThe SynGAP1 missense variant Y39D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Y39D, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.432876 | Uncertain | 0.343 | 0.787 | 0.375 | -2.338 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -1.86 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 0.4099 | 0.0903 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.1285C>G | R429G 2D 3DClick to see structure in 3D Viewer AISynGAP1 R429G 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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 uncertain. No evidence from FoldX or Rosetta is available. Overall, the predictions are evenly split, with no clear consensus. The variant is most likely of uncertain significance; it is not contradicted by ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | -9.157 | Likely Pathogenic | 0.333 | Likely Benign | Likely Benign | 1.58 | Ambiguous | 0.0 | 1.68 | Ambiguous | 1.63 | Ambiguous | 1.21 | Destabilizing | 0.257 | Likely Benign | -3.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.34 | Tolerated | 0.2888 | 0.2717 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.2920G>C | D974H 2D AIThe SynGAP1 missense variant D974H 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, 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.034 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.95 | Neutral | 0.744 | Possibly Damaging | 0.382 | Benign | 4.14 | Benign | 0.02 | Affected | 0.2249 | 0.7803 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3111C>G | I1037M 2D AIThe SynGAP1 missense variant I1037M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -3.849 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.40 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.71 | Benign | 0.18 | Tolerated | 0.0775 | 0.3885 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3926T>A | V1309E 2D AIThe SynGAP1 missense variant V1309E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 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 | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -3.393 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.294 | Likely Benign | -2.40 | Neutral | 0.767 | Possibly Damaging | 0.473 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.1098 | 0.1727 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.1688G>A | R563K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R563K 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, 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. Predictions that are inconclusive are Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as benign. Based on the overall consensus of 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 | GAP | 0.039760 | Structured | 0.031987 | Uncertain | 0.876 | 0.209 | 0.000 | -10.948 | Likely Pathogenic | 0.335 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.0 | 0.66 | Ambiguous | 0.46 | Likely Benign | 0.70 | Ambiguous | 0.198 | Likely Benign | -2.37 | Neutral | 0.990 | Probably Damaging | 0.998 | Probably Damaging | 3.46 | Benign | 0.35 | Tolerated | 0.4434 | 0.2379 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||
| c.2180A>C | N727T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N727T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. FoldX gives an uncertain result and is therefore treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | -6.900 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.1 | -0.18 | Likely Benign | 0.17 | Likely Benign | 0.04 | Likely Benign | 0.125 | Likely Benign | -3.08 | Deleterious | 0.987 | Probably Damaging | 0.980 | Probably Damaging | 2.25 | Pathogenic | 0.74 | Tolerated | 0.1315 | 0.7181 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||
| c.2827G>C | G943R 2D AIThe SynGAP1 missense variant G943R is reported in gnomAD (variant ID 6-33443379‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity; only ESM1b is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports 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 available predictions strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443379-G-C | 1 | 6.20e-7 | -7.159 | In-Between | 0.335 | Likely Benign | Likely Benign | 0.308 | Likely Benign | 1.00 | Neutral | 0.411 | Benign | 0.062 | Benign | 2.86 | Benign | 0.94 | Tolerated | 4.32 | 4 | 0.0976 | 0.4933 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3126G>C | Q1042H 2D AIThe SynGAP1 missense variant Q1042H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.258 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2207 | 0.4671 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3126G>T | Q1042H 2D AIThe SynGAP1 missense variant Q1042H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.258 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2207 | 0.4671 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3875T>A | L1292H 2D AIThe SynGAP1 missense variant L1292H is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33447923‑T‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with a slight tilt toward pathogenicity (five pathogenic vs. four benign). Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | 6-33447923-T-A | -5.692 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -4.42 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1271 | 0.0649 | -3 | -2 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||
| c.883A>T | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); 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 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 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.218 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>G | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); 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 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 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.196 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1586T>C | I529T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification—there is no contradiction between the predictions and the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | Uncertain | 1 | -0.539 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.16 | Likely Benign | 0.19 | Likely Benign | 0.17 | Likely Benign | 0.343 | Likely Benign | 0.24 | Neutral | 0.872 | Possibly Damaging | 0.820 | Possibly Damaging | -1.23 | Pathogenic | 0.55 | Tolerated | 3.37 | 35 | 0.0897 | 0.0989 | 0 | -1 | -5.2 | -12.05 | 207.2 | 29.8 | 0.2 | 0.0 | 0.2 | 0.1 | X | Potentially Benign | Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||||
| c.2971G>T | G991W 2D AIThe SynGAP1 missense variant G991W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -6.281 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.32 | Neutral | 0.997 | Probably Damaging | 0.975 | Probably Damaging | 4.07 | Benign | 0.00 | Affected | 0.0745 | 0.3654 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3355G>T | G1119W 2D AIThe SynGAP1 missense variant G1119W is reported in gnomAD (ID 6‑33443907‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion 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 Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443907-G-T | -10.904 | Likely Pathogenic | 0.336 | Likely Benign | Likely Benign | 0.386 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.949 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 4.32 | 2 | 0.0948 | 0.4059 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| c.883A>G | T295A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (REVEL, FoldX, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). Four tools are uncertain (Rosetta, Foldetta, premPS, ESM1b). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus indicates a pathogenic signal. Thus, the variant is most likely benign based on the bulk of evidence, 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. | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -7.276 | In-Between | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 1.17 | Ambiguous | 0.70 | Ambiguous | 0.56 | Ambiguous | 0.340 | Likely Benign | -3.51 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.96 | Pathogenic | 0.11 | Tolerated | 0.4623 | 0.4190 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, 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 | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | 0.730 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2343 | 0.0746 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | |||||||||||||
| c.236A>T | N79I 2D AIThe SynGAP1 missense variant N79I 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 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 annotation (none is present). 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 | -3.958 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.42 | Neutral | 0.939 | Possibly Damaging | 0.080 | Benign | 4.14 | Benign | 0.00 | Affected | 0.0572 | 0.4924 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3279G>C | Q1093H 2D AIThe SynGAP1 missense variant Q1093H 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 preponderance of 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1600 | 0.5269 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3279G>T | Q1093H 2D AIThe SynGAP1 missense variant Q1093H 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 preponderance of 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1600 | 0.5269 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.391G>A | G131S 2D AIThe SynGAP1 missense variant G131S 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, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -2.953 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -2.75 | Deleterious | 0.115 | Benign | 0.026 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2823 | 0.5338 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.1834C>G | Q612E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). In silico predictors that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictors that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta are inconclusive, with Foldetta specifically yielding an uncertain stability change. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of consensus‑based and high‑accuracy predictions lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current 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 | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -12.179 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.4 | 1.01 | Ambiguous | 0.77 | Ambiguous | 1.03 | Destabilizing | 0.423 | Likely Benign | -2.89 | Deleterious | 0.995 | Probably Damaging | 0.981 | Probably Damaging | -1.17 | Pathogenic | 0.26 | Tolerated | 0.1393 | 0.2099 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| 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.2245C>T | R749W 2D AIThe SynGAP1 missense variant R749W is listed in ClinVar as benign and is observed in gnomAD (ID 6‑33441710‑C‑T). Prediction tools that classify the variant as benign include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta stability analysis is unavailable. Overall, the majority of evidence, especially from high‑confidence methods, supports a benign effect. This consensus aligns with the ClinVar designation, so there is no contradiction between the predictions and the reported clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441710-C-T | 3 | 1.86e-6 | -7.647 | In-Between | 0.338 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.62 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1215 | 0.4088 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2306T>C | L769P 2D AIThe SynGAP1 missense variant L769P 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 from 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 this 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 | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.261 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -1.75 | Neutral | 0.925 | Possibly Damaging | 0.427 | Benign | 3.90 | Benign | 0.00 | Affected | 0.3573 | 0.1323 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.256G>A | V86I 2D  AIThe SynGAP1 missense variant V86I is listed in ClinVar (ID 588267.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign or likely benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the majority of predictions indicate that V86I is most likely benign, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.685117 | Disordered | 0.552911 | Binding | 0.295 | 0.887 | 0.500 | Uncertain | 1 | -4.726 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.31 | Neutral | 0.267 | Benign | 0.097 | Benign | 3.94 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0887 | 0.4417 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.275G>T | G92V 2D AIThe SynGAP1 missense variant G92V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, 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 further support a benign outcome: 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 impact for G92V, 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 | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | -4.627 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.972 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 0.1171 | 0.4363 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>A | S1013Y 2D AIThe SynGAP1 missense variant S1013Y 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. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -4.882 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.78 | Neutral | 0.290 | Benign | 0.124 | Benign | 2.66 | Benign | 0.03 | Affected | 0.0954 | 0.5629 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3217T>C | S1073P 2D AIThe SynGAP1 missense variant S1073P is reported in gnomAD (variant ID 6‑33443769‑T‑C) 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 preponderance of evidence points to a benign impact for S1073P, 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 | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | 6-33443769-T-C | 1 | 6.23e-7 | -4.520 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.76 | Neutral | 0.006 | Benign | 0.008 | Benign | 3.85 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2243 | 0.5900 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.3356G>A | G1119E 2D AIThe SynGAP1 missense variant G1119E is reported in gnomAD (variant ID 6-33443908‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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 G1119E is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443908-G-A | 1 | 6.61e-7 | -9.151 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | 0.284 | Likely Benign | -0.41 | Neutral | 0.005 | Benign | 0.013 | Benign | 3.93 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.1654 | 0.4259 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.4015A>C | N1339H 2D AIThe SynGAP1 missense variant N1339H 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, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, SGM‑Consensus likewise indicates likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this assessment 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 | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -3.487 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.987 | Probably Damaging | 2.87 | Benign | 0.00 | Affected | 0.1585 | 0.7644 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.595A>G | N199D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus classify the variant as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. The only inconclusive results come from ESM1b and Rosetta, which are treated as unavailable. 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 “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign outcome. 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 | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -7.874 | In-Between | 0.338 | Likely Benign | Likely Benign | -0.14 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.41 | Likely Benign | 0.13 | Likely Benign | 0.028 | Likely Benign | -1.41 | Neutral | 0.276 | Benign | 0.062 | Benign | 4.22 | Benign | 0.35 | Tolerated | 0.1516 | 0.3514 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.119A>C | D40A 2D AIThe SynGAP1 missense variant D40A 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 the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Taken together, the majority of evidence supports a benign interpretation, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.630 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.22 | Neutral | 0.006 | Benign | 0.023 | Benign | 4.05 | Benign | 0.00 | Affected | 0.4299 | 0.7993 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>T | Q756L 2D AIThe SynGAP1 missense variant Q756L 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 labeled “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 Q756L, 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 | -3.697 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.274 | Likely Benign | -1.95 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.56 | Pathogenic | 0.08 | Tolerated | 0.0797 | 0.5700 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2980A>G | K994E 2D AIThe SynGAP1 missense variant K994E is reported in gnomAD (variant ID 6‑33443532‑A‑G) 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 tools, including the high‑accuracy methods, points to a benign impact. This prediction 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 | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | 6-33443532-A-G | 1 | 6.20e-7 | -2.587 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.14 | Benign | 0.02 | Affected | 4.32 | 2 | 0.4148 | 0.1699 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||
| c.3172G>C | G1058R 2D AIThe SynGAP1 missense variant G1058R 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), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two predictors—SIFT and ESM1b—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -8.967 | Likely Pathogenic | 0.339 | Likely Benign | Likely Benign | 0.138 | Likely Benign | 0.34 | Neutral | 0.174 | Benign | 0.140 | Benign | 5.29 | Benign | 0.00 | Affected | 0.1145 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.943A>T | N315Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315Y 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The 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 uncertain. Overall, the balance of evidence slightly favors a pathogenic interpretation, with six pathogenic‑predicted tools versus five benign‑predicted tools, and the high‑accuracy consensus leaning pathogenic. 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 | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -8.303 | Likely Pathogenic | 0.339 | Likely Benign | Likely Benign | -1.03 | Ambiguous | 0.5 | -0.85 | Ambiguous | -0.94 | Ambiguous | -0.10 | Likely Benign | 0.420 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.93 | Pathogenic | 1.00 | Tolerated | 0.0613 | 0.6732 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| 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.2482A>G | T828A 2D AIThe SynGAP1 missense variant T828A is reported in gnomAD (variant ID 6‑33443034‑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 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 reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar classification (none is present). 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 | 6-33443034-A-G | 1 | 6.20e-7 | -2.974 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.13 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.24 | Tolerated | 3.77 | 5 | 0.4039 | 0.3861 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2696T>G | I899S 2D  AIThe SynGAP1 missense variant I899S 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 the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar record, which contains no assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.443727 | Uncertain | 0.292 | 0.928 | 0.375 | -0.857 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.38 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.88 | Benign | 0.00 | Affected | 0.2838 | 0.0840 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>G | H1030R 2D AIThe SynGAP1 missense variant H1030R is not reported in ClinVar and is absent from gnomAD. 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. 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) is “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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.312 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -1.08 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.85 | Benign | 0.06 | Tolerated | 0.1872 | 0.2955 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3142G>T | G1048W 2D AIThe SynGAP1 missense variant G1048W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, 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 | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -8.803 | Likely Pathogenic | 0.340 | Likely Benign | Likely Benign | 0.498 | Likely Benign | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0852 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| 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.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.2972G>A | G991E 2D AIThe SynGAP1 missense variant G991E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -4.729 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.30 | Neutral | 0.846 | Possibly Damaging | 0.697 | Possibly Damaging | 4.13 | Benign | 0.01 | Affected | 0.1480 | 0.4277 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3103C>T | P1035S 2D AIThe SynGAP1 missense variant P1035S 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 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. Taken together, the preponderance of evidence points to a benign impact for P1035S, 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -3.678 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.059 | Likely Benign | -0.97 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.79 | Benign | 0.28 | Tolerated | 0.3257 | 0.6253 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.1465C>A | L489I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is indeterminate due to a tie between pathogenic and benign signals, and Foldetta reports an uncertain stability change. Overall, the preponderance 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. | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -7.333 | In-Between | 0.342 | Ambiguous | Likely Benign | 1.01 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.77 | Ambiguous | 0.90 | Ambiguous | 0.490 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.21 | Tolerated | 0.1069 | 0.4080 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.3179G>A | G1060D 2D AIThe SynGAP1 missense variant G1060D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign (2 benign vs 1 pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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. | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.824 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -0.58 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.63 | Benign | 0.20 | Tolerated | 0.1703 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3203T>G | L1068W 2D AIThe SynGAP1 missense variant L1068W is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves as pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for L1068W. 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. | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -8.574 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -1.96 | Neutral | 0.994 | Probably Damaging | 0.884 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.0742 | 0.3763 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3949G>T | G1317C 2D AIThe SynGAP1 missense variant G1317C is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451823‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the majority of reliable predictions favor a benign impact, and this is consistent with the lack of ClinVar evidence. 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. | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | 6-33451823-G-T | -5.850 | Likely Benign | 0.342 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -3.83 | Deleterious | 0.939 | Possibly Damaging | 0.570 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1345 | 0.3753 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||
| c.931C>T | H311Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311Y 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, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools with uncertain or inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Default—are treated as unavailable for pathogenicity assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the predictions are split, with five tools favoring benign, five favoring pathogenic, and three inconclusive. Based on the available evidence, the variant is most likely pathogenic, and this assessment 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. | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -4.513 | Likely Benign | 0.342 | Ambiguous | Likely Benign | -0.06 | Likely Benign | 0.2 | -1.58 | Ambiguous | -0.82 | Ambiguous | 0.18 | Likely Benign | 0.456 | Likely Benign | -3.80 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.86 | Pathogenic | 0.02 | Affected | 0.0965 | 0.4180 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.1211C>T | A404V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A404V missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438116‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and ESM1b. Four tools (FoldX, Rosetta, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, though a key consensus method suggests pathogenicity, leaving the variant’s effect unresolved. **The variant is most likely benign based on the prevailing predictions, and this assessment does not contradict ClinVar status, as no ClinVar classification exists.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | 6-33438116-C-T | 1 | 6.20e-7 | -8.219 | Likely Pathogenic | 0.343 | Ambiguous | Likely Benign | 0.56 | Ambiguous | 0.3 | -1.55 | Ambiguous | -0.50 | Ambiguous | -0.05 | Likely Benign | 0.118 | Likely Benign | -2.96 | Deleterious | 0.345 | Benign | 0.018 | Benign | 4.20 | Benign | 0.47 | Tolerated | 3.38 | 28 | 0.1288 | 0.6842 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.218G>C | R73T 2D AIThe SynGAP1 missense variant R73T 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. 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, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable and therefore not considered. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods indicates that R73T 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 | 0.501700 | Disordered | 0.453164 | Uncertain | 0.332 | 0.826 | 0.375 | -4.061 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -1.05 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.05 | Benign | 0.00 | Affected | 0.1980 | 0.4439 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2215G>A | E739K 2D AIThe SynGAP1 missense variant E739K 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | -5.420 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.107 | Likely Benign | -1.49 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.55 | Benign | 0.00 | Affected | 0.2697 | 0.7044 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2839G>A | G947R 2D AIThe SynGAP1 missense variant G947R is listed in gnomAD (6-33443391-G-A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) and pathogenic (SIFT). Two tools remain uncertain (ESM1b, AlphaMissense‑Default). High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—does not reach a definitive conclusion (two benign, two uncertain). Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the preponderance of evidence points to a benign impact, 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. | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | 6-33443391-G-A | 6 | 3.72e-6 | -7.481 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.273 | Likely Benign | -0.60 | Neutral | 0.411 | Benign | 0.140 | Benign | 4.94 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1034 | 0.4733 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2839G>C | G947R 2D AIThe SynGAP1 missense variant G947R 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, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. 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. | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -7.481 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.273 | Likely Benign | -0.60 | Neutral | 0.411 | Benign | 0.140 | Benign | 4.94 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1034 | 0.4733 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3181G>C | G1061R 2D AIThe SynGAP1 missense variant G1061R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -7.721 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.315 | Likely Benign | -0.17 | Neutral | 0.411 | Benign | 0.132 | Benign | 3.99 | Benign | 0.00 | Affected | 0.1037 | 0.4332 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3409C>G | H1137D 2D AIThe SynGAP1 missense variant H1137D is not reported in ClinVar and has no allele in gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and SIFT, 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 outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for H1137D, 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 | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -4.934 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.418 | Likely Benign | -2.26 | Neutral | 0.802 | Possibly Damaging | 0.430 | Benign | 5.56 | Benign | 0.00 | Affected | 0.2519 | 0.2916 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3883C>A | Q1295K 2D AIThe SynGAP1 missense variant Q1295K is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33447931‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic prediction (2 pathogenic vs. 1 benign vs. 1 uncertain). AlphaMissense‑Optimized remains benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) point to a pathogenic effect. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447931-C-A | -3.419 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.313 | Likely Benign | -3.30 | Deleterious | 0.843 | Possibly Damaging | 0.893 | Possibly Damaging | 2.38 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1782 | 0.3517 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||
| c.1121C>A | S374Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S374Y 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, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, whereas polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. Uncertain calls come from FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta likewise yields an uncertain stability change. Overall, the majority of available predictions favor 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. | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | Uncertain | 1 | -7.774 | In-Between | 0.344 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 1.2 | 0.66 | Ambiguous | 0.69 | Ambiguous | -0.02 | Likely Benign | 0.310 | Likely Benign | -1.18 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 5.41 | Benign | 0.01 | Affected | 4.32 | 13 | 0.1175 | 0.6705 | -3 | -2 | -0.5 | 76.10 | 237.3 | -76.9 | 0.5 | 0.4 | 0.5 | 0.3 | Uncertain | Ser374 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus, large and relatively hydrophobic residues like tyrosine are rarely tolerated. Additionally, the hydroxyl group of Tyr374 frequently forms various hydrogen bonds with other loop residues in the variant simulations. Although no negative structural effects are observed in the variant simulations, Tyr374 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||||
| c.214C>G | R72G 2D AIThe SynGAP1 missense variant R72G 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar classification; there is no contradiction with ClinVar status. 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 | -3.580 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.121 | Likely Benign | -0.93 | Neutral | 0.686 | Possibly Damaging | 0.250 | Benign | 4.11 | Benign | 0.00 | Affected | 0.3900 | 0.2847 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| 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.3226T>G | L1076V 2D AIThe SynGAP1 missense variant L1076V is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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 is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -3.615 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.56 | Neutral | 0.995 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.11 | Tolerated | 0.1632 | 0.3781 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.694G>T | A232S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Across the evaluated in‑silico predictors, all tools except AlphaMissense‑Default converge on a benign interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict benign. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. 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 Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign based on the collective 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 | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -3.264 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | -0.23 | Likely Benign | 0.00 | Likely Benign | -0.20 | Likely Benign | 0.378 | Likely Benign | 0.54 | Neutral | 0.057 | Benign | 0.025 | Benign | 5.95 | Benign | 1.00 | Tolerated | 0.2777 | 0.5300 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.805A>G | I269V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269V missense variant has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools lean toward a benign interpretation, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s clinical significance uncertain. This assessment does not contradict any existing ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -8.748 | Likely Pathogenic | 0.344 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.72 | Ambiguous | 0.71 | Ambiguous | 0.393 | Likely Benign | -0.72 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 1.87 | Pathogenic | 0.10 | Tolerated | 0.0844 | 0.2859 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.166C>A | L56M 2D AIThe SynGAP1 missense variant L56M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b 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) is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence (four benign versus three pathogenic predictions, with two uncertain) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.342579 | Structured | 0.476218 | Uncertain | 0.495 | 0.657 | 0.000 | -7.470 | In-Between | 0.345 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -0.51 | Neutral | 0.824 | Possibly Damaging | 0.910 | Probably Damaging | 3.86 | Benign | 0.00 | Affected | 0.0797 | 0.3574 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2107C>A | L703I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and Rosetta. Predictions that are uncertain or inconclusive (FoldX, Foldetta, premPS, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of high‑confidence tools predict a benign impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -9.332 | Likely Pathogenic | 0.345 | Ambiguous | Likely Benign | 1.44 | Ambiguous | 0.1 | 2.21 | Destabilizing | 1.83 | Ambiguous | 0.61 | Ambiguous | 0.108 | Likely Benign | -1.50 | Neutral | 0.982 | Probably Damaging | 0.758 | Possibly Damaging | 3.38 | Benign | 0.00 | Affected | 0.0909 | 0.3079 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2545G>C | D849H 2D AIThe SynGAP1 missense variant D849H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.554191 | Binding | 0.319 | 0.813 | 0.500 | -4.624 | Likely Benign | 0.345 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -0.52 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.14 | Benign | 0.00 | Affected | 0.1977 | 0.8673 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3229A>C | T1077P 2D AIThe SynGAP1 missense variant T1077P is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence shows AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of predictions and the high‑accuracy consensus point to a benign impact. This conclusion is not contradicted by ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -2.436 | Likely Benign | 0.345 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -0.91 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.16 | Benign | 0.04 | Affected | 0.1876 | 0.4788 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3371G>A | G1124E 2D AIThe SynGAP1 missense variant G1124E 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome (2 benign vs. 1 pathogenic votes). 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 the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -10.403 | Likely Pathogenic | 0.345 | Ambiguous | Likely Benign | 0.301 | Likely Benign | -0.84 | Neutral | 0.126 | Benign | 0.066 | Benign | 4.78 | Benign | 0.02 | Affected | 0.1405 | 0.4063 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2014A>C | T672P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T672P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact for T672P. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | -11.022 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 2.22 | Destabilizing | 0.2 | 5.54 | Destabilizing | 3.88 | Destabilizing | 0.55 | Ambiguous | 0.087 | Likely Benign | -4.20 | Deleterious | 0.968 | Probably Damaging | 0.824 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.1988 | 0.5532 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.2996C>A | S999Y 2D AIThe SynGAP1 missense variant S999Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999Y, 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.446 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.74 | Neutral | 0.934 | Possibly Damaging | 0.559 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0881 | 0.6249 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3151G>C | G1051R 2D AIThe SynGAP1 missense variant G1051R 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Two tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains one pathogenic, one benign, and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -7.907 | In-Between | 0.346 | Ambiguous | Likely Benign | 0.438 | Likely Benign | 0.20 | Neutral | 0.761 | Possibly Damaging | 0.305 | Benign | -0.74 | Pathogenic | 0.20 | Tolerated | 0.0956 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3182G>A | G1061D 2D AIThe SynGAP1 missense variant G1061D 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -9.481 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 0.375 | Likely Benign | -1.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1671 | 0.2024 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3586A>C | K1196Q 2D AIThe SynGAP1 missense variant K1196Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -5.222 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.342 | Likely Benign | -0.65 | Neutral | 0.989 | Probably Damaging | 0.819 | Possibly Damaging | 5.38 | Benign | 0.07 | Tolerated | 0.3814 | 0.0945 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.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.2755C>A | Q919K 2D AIThe SynGAP1 missense variant Q919K 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 majority of evidence supports a benign interpretation, 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 | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -4.357 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -1.43 | Neutral | 0.771 | Possibly Damaging | 0.412 | Benign | 2.54 | Benign | 0.21 | Tolerated | 0.1950 | 0.4000 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.296A>C | E99A 2D  AIThe SynGAP1 E99A missense change is not reported in ClinVar and has no entry in gnomAD. Consensus‑based predictors cluster around a benign interpretation: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all score the variant as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” verdict. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools therefore converge on a benign prediction: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. 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 | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.173 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.49 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.07 | Benign | 0.00 | Affected | 0.4245 | 0.7548 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.850C>G | L284V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284V missense variant has no ClinVar entry and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, AlphaMissense‑Default, and Foldetta. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the balance of evidence leans toward a pathogenic effect, and this assessment 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. | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -6.726 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 1.65 | Ambiguous | 0.2 | 2.08 | Destabilizing | 1.87 | Ambiguous | 1.38 | Destabilizing | 0.248 | Likely Benign | -2.32 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.18 | Pathogenic | 0.03 | Affected | 0.1259 | 0.2456 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1070A>G | H357R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H357R 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, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Two tools remain uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority; and Foldetta also predicts benign. No prediction or stability result is missing or inconclusive. 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. | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -9.212 | Likely Pathogenic | 0.348 | Ambiguous | Likely Benign | -0.10 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.49 | Likely Benign | 0.32 | Likely Benign | 0.107 | Likely Benign | -1.03 | Neutral | 0.495 | Possibly Damaging | 0.095 | Benign | 4.22 | Benign | 0.59 | Tolerated | 0.2147 | 0.2818 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||
| 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.2809G>A | D937N 2D AIThe SynGAP1 missense variant D937N 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further corroborate this view: AlphaMissense‑Optimized indicates benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact for D937N, 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 | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -4.259 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -0.22 | Neutral | 0.561 | Possibly Damaging | 0.139 | Benign | 2.72 | Benign | 0.81 | Tolerated | 0.2430 | 0.7825 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>A | M1148I 2D AIThe SynGAP1 missense variant M1148I 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, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized. Only SIFT 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. There is no ClinVar annotation to contradict this conclusion, so 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 | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>C | M1148I 2D AIThe SynGAP1 missense variant M1148I has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized all indicate a benign or likely benign outcome. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus also reports likely benign, and Foldetta data are unavailable. Based on the preponderance of evidence, the variant is most likely benign, 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 Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>T | M1148I 2D AIThe SynGAP1 missense variant M1148I has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized all indicate a benign or likely benign outcome. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus also reports likely benign, and Foldetta data are unavailable. Based on the preponderance of evidence, the variant is most likely benign, 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 Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3884A>T | Q1295L 2D AIThe SynGAP1 missense variant Q1295L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for Q1295L, 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. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -2.862 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.379 | Likely Benign | -5.63 | Deleterious | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.0810 | 0.5672 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.1846G>A | D616N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into benign (REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b). Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta remains uncertain. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus suggests pathogenicity, leaving the variant’s clinical significance ambiguous. Based on the prevailing evidence, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -8.292 | Likely Pathogenic | 0.349 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.2 | 1.05 | Ambiguous | 0.80 | Ambiguous | 0.03 | Likely Benign | 0.149 | Likely Benign | -3.74 | Deleterious | 0.875 | Possibly Damaging | 0.581 | Possibly Damaging | 3.41 | Benign | 0.11 | Tolerated | 0.1053 | 0.3976 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.2189T>G | I730S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I730S 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‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all uniformly predict a benign impact. Based on the collective evidence, the variant is most likely benign, 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 | 0.733139 | Disordered | 0.420109 | Uncertain | 0.591 | 0.619 | 0.750 | -6.220 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.25 | Likely Benign | 0.2 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.47 | Likely Benign | 0.123 | Likely Benign | -0.51 | Neutral | 1.000 | Probably Damaging | 0.967 | Probably Damaging | 3.60 | Benign | 0.34 | Tolerated | 0.2646 | 0.0903 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||
| 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.2491G>C | E831Q 2D AIThe SynGAP1 missense variant E831Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy methods give a benign prediction from AlphaMissense‑Optimized and a benign consensus from SGM; Foldetta results are unavailable. Overall, the available computational evidence points to a benign impact for E831Q, and this assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.626927 | Disordered | 0.617732 | Binding | 0.319 | 0.874 | 0.375 | -5.604 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -1.23 | Neutral | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 2.36 | Pathogenic | 0.09 | Tolerated | 0.1022 | 0.7052 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.286G>C | G96R 2D AIThe SynGAP1 missense variant G96R 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G96R, 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 | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | -3.872 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.059 | Likely Benign | -0.91 | Neutral | 0.687 | Possibly Damaging | 0.062 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1300 | 0.5031 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3148G>A | G1050R 2D AIThe SynGAP1 missense variant G1050R is catalogued in gnomAD (ID 6‑33443700‑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, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | 6-33443700-G-A | 3 | 1.86e-6 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3148G>C | G1050R 2D AIThe SynGAP1 missense variant G1050R 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, SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2591C>A | A864E 2D AIThe SynGAP1 missense variant A864E 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, which evaluates protein‑folding stability, 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 and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | -5.508 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.153 | Likely Benign | 0.10 | Neutral | 0.138 | Benign | 0.070 | Benign | 2.45 | Pathogenic | 0.04 | Affected | 0.1204 | 0.2037 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.608A>G | D203G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (two benign vs. one pathogenic, one uncertain); and Foldetta also predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a benign effect, and this is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -6.332 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.40 | Likely Benign | 0.03 | Likely Benign | 0.231 | Likely Benign | -3.42 | Deleterious | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 0.2708 | 0.4312 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.864C>A | D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta 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 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 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -6.685 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.42 | Likely Benign | -0.10 | Likely Benign | 0.203 | Likely Benign | -2.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.13 | Tolerated | 0.1559 | 0.5476 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.864C>G | D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta 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 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 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -6.685 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.42 | Likely Benign | -0.10 | Likely Benign | 0.203 | Likely Benign | -2.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.13 | Tolerated | 0.1559 | 0.5476 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| 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.2548G>T | G850W 2D AIThe SynGAP1 missense variant G850W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b 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) is inconclusive (two benign, two uncertain), and Foldetta data are unavailable. Overall, the balance of evidence (four benign vs. three pathogenic predictions, with a benign high‑accuracy result and no contradictory ClinVar annotation) indicates that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -7.826 | In-Between | 0.351 | Ambiguous | Likely Benign | 0.170 | Likely Benign | -1.94 | Neutral | 0.996 | Probably Damaging | 0.933 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | 0.0734 | 0.4002 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2576G>T | S859I 2D AIThe SynGAP1 missense variant S859I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of computational evidence indicates a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar record exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -8.342 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.256 | Likely Benign | -1.94 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 3.99 | Benign | 0.02 | Affected | 0.1094 | 0.5867 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2921A>T | D974V 2D AIThe SynGAP1 missense variant D974V 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. 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, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective predictions strongly suggest that D974V 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.629 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.211 | Likely Benign | -1.49 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.16 | Benign | 0.01 | Affected | 0.1449 | 0.7286 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3064C>T | L1022F 2D AIThe SynGAP1 missense variant L1022F is reported in gnomAD (variant ID 6‑33443616‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | 6-33443616-C-T | 2 | 1.24e-6 | -5.035 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.84 | Neutral | 0.971 | Probably Damaging | 0.801 | Possibly Damaging | 2.51 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.0730 | 0.4231 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||
| c.3161G>A | G1054D 2D AISynGAP1 missense variant G1054D 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, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Uncertain | 1 | -10.385 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.279 | Likely Benign | -0.26 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.07 | Benign | 0.37 | Tolerated | 3.77 | 5 | 0.1824 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.527G>C | S176T 2D AIThe SynGAP1 missense variant S176T 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 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, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, 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 Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -3.682 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.73 | Neutral | 0.421 | Benign | 0.054 | Benign | 4.09 | Benign | 0.19 | Tolerated | 0.1103 | 0.4979 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>G | Q920R 2D AIThe SynGAP1 missense variant Q920R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy tools further support this view: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms 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 preponderance of 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.170 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -1.41 | Neutral | 0.961 | Probably Damaging | 0.596 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1626 | 0.2369 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3422C>T | P1141L 2D AIThe SynGAP1 missense variant P1141L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic versus one benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that P1141L is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -3.817 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -4.64 | Deleterious | 0.954 | Possibly Damaging | 0.759 | Possibly Damaging | 0.98 | Pathogenic | 0.00 | Affected | 0.2147 | 0.6099 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.59C>A | P20H 2D AIThe SynGAP1 missense variant P20H is reported in gnomAD (ID 6‑33420323‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates benign. Foldetta results are unavailable. Overall, the preponderance of evidence from both consensus and high‑accuracy tools points to a benign effect for P20H, and this conclusion does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | 6-33420323-C-A | -4.450 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -0.69 | Neutral | 0.992 | Probably Damaging | 0.893 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1834 | 0.5066 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.62T>A | F21Y 2D AIThe SynGAP1 missense variant F21Y is listed in gnomAD (ID 6‑33420326‑T‑A) 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign classification. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for F21Y, 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 | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | 6-33420326-T-A | -3.712 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.088 | Likely Benign | -0.23 | Neutral | 0.273 | Benign | 0.153 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1698 | 0.2608 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.740A>T | Q247L 2D AIThe SynGAP1 missense variant Q247L 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence (seven pathogenic versus three benign predictions) points to a pathogenic impact, and 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. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -10.554 | Likely Pathogenic | 0.352 | Ambiguous | Likely Benign | -0.86 | Ambiguous | 0.5 | -1.14 | Ambiguous | -1.00 | Ambiguous | 0.38 | Likely Benign | 0.687 | Likely Pathogenic | -3.89 | Deleterious | 0.982 | Probably Damaging | 0.628 | Possibly Damaging | 5.70 | Benign | 0.02 | Affected | 0.0573 | 0.4129 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.2375A>G | E792G 2D AIThe SynGAP1 E792G 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 and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic vote). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta results are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion 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. | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | -3.925 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.037 | Likely Benign | -3.77 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.88 | Benign | 0.01 | Affected | 0.3145 | 0.6036 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>T | S1013F 2D AIThe SynGAP1 missense variant S1013F is catalogued in gnomAD (ID 6‑33443590‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen2_HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen2_HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to mixed signals, and Foldetta results are unavailable. Overall, the balance of evidence, including the benign call from AlphaMissense‑Optimized, points to a likely benign effect. 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. | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | 6-33443590-C-T | 1 | 6.20e-7 | -5.370 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -2.54 | Deleterious | 0.453 | Possibly Damaging | 0.272 | Benign | 2.65 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0922 | 0.5803 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3184G>A | G1062R 2D AIThe SynGAP1 missense variant G1062R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443736‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, polyPhen‑2 HumVar, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | Conflicting | 2 | 6-33443736-G-A | 7 | 4.35e-6 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3184G>C | G1062R 2D AIThe SynGAP1 missense variant G1062R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.413 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3374G>A | G1125E 2D AIThe SynGAP1 missense variant G1125E is not reported in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID 6‑33443926‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, AlphaMissense‑Optimized, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, and 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 available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443926-G-A | 11 | 7.34e-6 | -9.849 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | 0.264 | Likely Benign | -0.32 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.58 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1430 | 0.4063 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||
| c.899C>T | S300F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S300F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The remaining tool, AlphaMissense‑Default, gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, while two high‑accuracy methods support a benign effect. Thus, the variant is most likely pathogenic based on the current computational evidence, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | Uncertain | 1 | -10.222 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | -0.29 | Likely Benign | 0.4 | 0.16 | Likely Benign | -0.07 | Likely Benign | 0.04 | Likely Benign | 0.117 | Likely Benign | -2.66 | Deleterious | 0.975 | Probably Damaging | 0.596 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.47 | 19 | 0.0579 | 0.5701 | -3 | -2 | 3.6 | 60.10 | 233.6 | -67.6 | -0.1 | 0.0 | 0.4 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl group of the Ser300 side chain, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), hydrogen bonds with the guanidinium group of Arg299 and the backbone amide group and side chain of Ser302. Thus, in the WT simulations, it contributes to the β hairpin stability. In the variant simulations, the phenol ring of Phe300 cannot form any side chain-related hydrogen bonds, and Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, 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 | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | 0.1872 | 0.2452 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||
| c.1208A>G | K403R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403R 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, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools—FoldX, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a tie, and Foldetta also predicts benign. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -7.362 | In-Between | 0.355 | Ambiguous | Likely Benign | -0.78 | Ambiguous | 0.1 | 0.23 | Likely Benign | -0.28 | Likely Benign | 0.41 | Likely Benign | 0.335 | Likely Benign | -2.56 | Deleterious | 0.983 | Probably Damaging | 0.926 | Probably Damaging | 3.91 | Benign | 0.15 | Tolerated | 0.4834 | 0.1861 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.905C>A | S302Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302Y 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 HumVar, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, and ESM1b. Two tools give uncertain results: AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. 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. | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.674 | Likely Pathogenic | 0.355 | Ambiguous | Likely Benign | -0.02 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.27 | Likely Benign | -0.17 | Likely Benign | 0.070 | Likely Benign | -1.03 | Neutral | 0.801 | Possibly Damaging | 0.383 | Benign | 4.07 | Benign | 0.01 | Affected | 0.0882 | 0.5990 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.1482A>G | I494M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools predicting a deleterious effect. 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 | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -8.223 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.35 | Likely Benign | 0.2 | 1.98 | Ambiguous | 1.17 | Ambiguous | 0.98 | Ambiguous | 0.542 | Likely Pathogenic | -2.25 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.15 | Pathogenic | 0.23 | Tolerated | 0.0676 | 0.1789 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.2365C>A | P789T 2D AIThe SynGAP1 P789T missense variant has no ClinVar entry and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized predicts a benign outcome, whereas 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, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that P789T is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is reported. 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 | -5.242 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.224 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.1371 | 0.3837 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2962C>T | L988F 2D AIThe SynGAP1 missense variant L988F is listed in ClinVar (ID 968833.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443514‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” 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. | Likely Benign | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | Uncertain | 1 | 6-33443514-C-T | 1 | 6.20e-7 | -4.368 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -1.70 | Neutral | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.69 | Benign | 0.00 | Affected | 4.32 | 2 | 0.0693 | 0.3592 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||
| c.3067T>G | S1023A 2D AIThe SynGAP1 missense variant S1023A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of pathogenic predictors—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT—suggest a damaging impact. The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy tools therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and no Foldetta data is available. Overall, the computational evidence supports a benign classification, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -6.031 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.098 | Likely Benign | -1.59 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.04 | Affected | 0.4427 | 0.4386 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3346G>T | G1116W 2D AIThe SynGAP1 missense variant G1116W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443898‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Taken together, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign effect. 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. | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443898-G-T | -9.448 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.405 | Likely Benign | -1.27 | Neutral | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0776 | 0.4046 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||
| c.668C>T | T223I 2D AIThe SynGAP1 T223I variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that clearly indicate benign impact include FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL and PROVEAN. Predictions that are inconclusive (Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of definitive predictions support a benign effect. Thus, 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. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -6.543 | Likely Benign | 0.356 | Ambiguous | Likely Benign | -0.24 | Likely Benign | 0.8 | -0.99 | Ambiguous | -0.62 | Ambiguous | 0.30 | Likely Benign | 0.640 | Likely Pathogenic | -4.09 | Deleterious | 0.010 | Benign | 0.005 | Benign | 5.93 | Benign | 0.07 | Tolerated | 0.0569 | 0.5393 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.100T>G | Y34D 2D AIThe SynGAP1 missense variant Y34D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.435847 | Uncertain | 0.303 | 0.855 | 0.375 | -2.653 | Likely Benign | 0.357 | Ambiguous | Likely Benign | 0.199 | Likely Benign | -1.20 | Neutral | 0.824 | Possibly Damaging | 0.828 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.4092 | 0.1322 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.328G>C | V110L 2D AIThe SynGAP1 missense variant V110L 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 and 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 combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence overwhelmingly supports a benign impact for V110L, 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 | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -3.024 | Likely Benign | 0.357 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -0.71 | Neutral | 0.158 | Benign | 0.025 | Benign | 4.20 | Benign | 0.50 | Tolerated | 0.1165 | 0.5145 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1919C>T | T640I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640I 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. The remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default, 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, and PROVEAN) is unavailable due to a tie, and Foldetta also yields an uncertain stability change. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -7.256 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.70 | Ambiguous | 0.1 | 0.66 | Ambiguous | 0.68 | Ambiguous | 0.28 | Likely Benign | 0.193 | Likely Benign | -2.75 | Deleterious | 0.322 | Benign | 0.022 | Benign | 3.46 | Benign | 0.12 | Tolerated | 0.1030 | 0.4793 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.223G>A | E75K 2D AIThe SynGAP1 missense variant E75K is listed in ClinVar as Benign (ClinVar ID 3360083.0) and is not reported in gnomAD. 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 effect 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 results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.443881 | Uncertain | 0.303 | 0.822 | 0.500 | Benign/Likely benign | 2 | -4.020 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.134 | Likely Benign | -1.12 | Neutral | 0.748 | Possibly Damaging | 0.017 | Benign | 4.07 | Benign | 0.00 | Affected | 0.2565 | 0.6908 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||
| c.2264T>C | M755T 2D AIThe SynGAP1 missense variant M755T 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, and FATHMM all classify the change as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta data are not available. Overall, the computational evidence overwhelmingly suggests 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -4.116 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.040 | Likely Benign | -1.23 | Neutral | 0.159 | Benign | 0.053 | Benign | 2.65 | Benign | 0.19 | Tolerated | 0.1944 | 0.1767 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.269T>G | V90G 2D AIThe SynGAP1 missense variant V90G 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 FATHMM. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.570702 | Disordered | 0.542047 | Binding | 0.343 | 0.873 | 0.500 | -2.617 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.094 | Likely Benign | -0.55 | Neutral | 0.024 | Benign | 0.208 | Benign | 4.00 | Benign | 0.00 | Affected | 0.2047 | 0.2936 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3350G>A | G1117D 2D AIThe SynGAP1 missense variant G1117D is catalogued in gnomAD (6‑33443902‑G‑A) but has no ClinVar entry. In silico predictors that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar classification (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | 6-33443902-G-A | 1 | 6.61e-7 | -7.594 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.315 | Likely Benign | -0.38 | Neutral | 0.666 | Possibly Damaging | 0.355 | Benign | 4.57 | Benign | 0.24 | Tolerated | 4.32 | 2 | 0.1920 | 0.2635 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3667C>A | L1223M 2D AIThe SynGAP1 missense variant L1223M is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also classifies the variant as benign, and Foldetta results are unavailable. Taken together, the balance of evidence favors a benign effect for L1223M, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.608892 | Disordered | 0.436267 | Uncertain | 0.868 | 0.540 | 0.375 | -5.759 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.166 | Likely Benign | -1.29 | Neutral | 0.981 | Probably Damaging | 0.752 | Possibly Damaging | 1.50 | Pathogenic | 0.04 | Affected | 0.0667 | 0.3014 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3889A>T | R1297W 2D AIThe SynGAP1 missense variant R1297W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is consistent with the lack of ClinVar reporting; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -6.039 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.262 | Likely Benign | -4.45 | Deleterious | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1260 | 0.2587 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.1322T>C | V441A 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V441A is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33438227‑T‑C). Consensus from most in silico predictors favors a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all report benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and ESM1b, while premPS and AlphaMissense‑Default remain uncertain. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | Conflicting | 2 | 6-33438227-T-C | 3 | 1.86e-6 | -9.439 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | -0.14 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.10 | Likely Benign | 0.95 | Ambiguous | 0.053 | Likely Benign | -2.92 | Deleterious | 0.513 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.93 | Tolerated | 3.37 | 29 | 0.2390 | 0.1800 | 0 | 0 | -2.4 | -28.05 | 195.0 | 44.6 | 0.0 | 0.1 | 0.5 | 0.0 | X | X | Uncertain | The iso-propyl side chain of Val441, located on the outer surface of an α helix (res. Asn440-Thr458), does not interact with other residues in the WT simulations. In the variant simulations, the methyl side chain of Ala441 is similarly hydrophobic and does not form any interactions on the outer helix surface. Although the residue swap does not negatively affect the protein structure based on the simulations, it is noteworthy that the residue faces the RasGTPase interface. Thus, the 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.2323C>G | R775G 2D AIThe SynGAP1 missense variant R775G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R775G, 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 | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | -4.186 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.118 | Likely Benign | -1.23 | Neutral | 0.933 | Possibly Damaging | 0.871 | Possibly Damaging | 4.12 | Benign | 0.07 | Tolerated | 0.3194 | 0.3761 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2830G>C | G944R 2D AIThe SynGAP1 missense variant G944R 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G944R, 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 | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.577 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.459 | Likely Benign | -1.82 | Neutral | 0.639 | Possibly Damaging | 0.299 | Benign | 3.73 | Benign | 0.00 | Affected | 0.1030 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3157A>C | S1053R 2D  AIThe SynGAP1 missense variant S1053R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority‑vote SGM‑Consensus also reports a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy analyses reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, with no contradictory Foldetta data. Overall, the preponderance of evidence points to a benign effect for S1053R, 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.225 | Likely Benign | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3159C>A | S1053R 2D AIThe SynGAP1 missense variant S1053R is reported in gnomAD (variant ID 6‑33443711‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, 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 AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. Overall, the majority of high‑accuracy predictors and consensus analyses indicate a benign impact. Thus, 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443711-C-A | 1 | 1.10e-6 | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.3159C>G | S1053R 2D AIThe SynGAP1 missense variant S1053R is reported in gnomAD (ID 6‑33443711‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the high‑accuracy consensus methods give a benign verdict: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443711-C-G | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.304 | Likely Benign | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3674C>A | S1225Y 2D AIThe SynGAP1 missense variant S1225Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -8.360 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.419 | Likely Benign | -2.27 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.34 | Benign | 0.04 | Affected | 0.0547 | 0.4691 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.1930G>A | D644N 2D AIThe SynGAP1 missense variant D644N 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all classifying the substitution as benign. No tool predicts pathogenicity. The only inconclusive result is AlphaMissense‑Default, which is listed as uncertain and therefore does not influence the overall assessment. High‑accuracy methods further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -4.389 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.06 | Likely Benign | 0.3 | -0.28 | Likely Benign | -0.11 | Likely Benign | 0.02 | Likely Benign | 0.124 | Likely Benign | -2.28 | Neutral | 0.007 | Benign | 0.001 | Benign | 3.45 | Benign | 0.25 | Tolerated | 0.1368 | 0.6261 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.3067T>A | S1023T 2D AIThe SynGAP1 missense variant S1023T 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, PROVEAN) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.573 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.04 | Affected | 0.1299 | 0.5370 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3644A>G | K1215R 2D AIThe SynGAP1 missense variant K1215R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data to contradict. 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 | Coiled-coil | 0.497853 | Structured | 0.503613 | Binding | 0.888 | 0.568 | 0.375 | -5.652 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -0.57 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.85 | Benign | 0.28 | Tolerated | 0.4051 | 0.0582 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.526A>G | S176G 2D AIThe SynGAP1 missense variant S176G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435168‑A‑G). Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all report a benign effect. No tool predicts pathogenicity. Two predictors are inconclusive: ESM1b and AlphaMissense‑Default, which are grouped under uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains uncertain, and Foldetta stability analysis is unavailable. Overall, the computational evidence overwhelmingly favors 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. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | 6-33435168-A-G | 1 | 6.20e-7 | -7.541 | In-Between | 0.360 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.08 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.08 | Benign | 0.22 | Tolerated | 3.54 | 6 | 0.2361 | 0.3414 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||
| c.92G>T | R31L 2D AIThe SynGAP1 missense variant R31L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict pathogenic. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically indicate benign: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta data are missing. Overall, the majority of reliable predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.147 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -1.79 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 0.2264 | 0.5148 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1354G>A | V452I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | 0.218 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 0.0630 | 0.3476 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||
| c.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.2330T>C | L777P 2D AIThe SynGAP1 missense variant L777P is catalogued in gnomAD (6‑33442488‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | 6-33442488-T-C | -5.807 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.255 | Likely Benign | -2.13 | Neutral | 0.991 | Probably Damaging | 0.985 | Probably Damaging | 3.94 | Benign | 0.00 | Affected | 3.64 | 6 | 0.3732 | 0.1664 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
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