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.1733A>C | E578A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E578A missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta also predicts benign. Overall, the majority of conventional tools lean benign, but the high‑accuracy consensus and AlphaMissense‑Optimized suggest a pathogenic effect. Thus, the variant is most likely pathogenic according to the most reliable predictors, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.059222 | Structured | 0.020971 | Uncertain | 0.902 | 0.240 | 0.000 | -7.369 | In-Between | 0.604 | Likely Pathogenic | Likely Benign | 0.34 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.07 | Likely Benign | -0.02 | Likely Benign | 0.525 | Likely Pathogenic | -2.30 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.40 | Pathogenic | 0.44 | Tolerated | 0.3326 | 0.5118 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.1774T>G | S592A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S592A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, SIFT, and AlphaMissense‑Optimized, whereas a majority (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.100070 | Uncertain | 0.913 | 0.182 | 0.000 | -10.902 | Likely Pathogenic | 0.572 | Likely Pathogenic | Likely Benign | -0.48 | Likely Benign | 0.1 | -0.93 | Ambiguous | -0.71 | Ambiguous | 0.79 | Ambiguous | 0.661 | Likely Pathogenic | -2.72 | Deleterious | 0.980 | Probably Damaging | 0.994 | Probably Damaging | -1.25 | Pathogenic | 0.44 | Tolerated | 0.4878 | 0.3318 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1963C>G | L655V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. 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, SGM‑Consensus indicates likely benign, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. No tools predict pathogenicity, and the uncertain stability assessment does not alter the overall benign inference. Therefore, based on the available predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | -6.743 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.78 | Ambiguous | 0.0 | 0.58 | Ambiguous | 0.68 | Ambiguous | 0.38 | Likely Benign | 0.058 | Likely Benign | -0.62 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.45 | Benign | 0.44 | Tolerated | 0.1551 | 0.3190 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2119G>A | A707T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A707T is reported in gnomAD (ID 6‑33441584‑G‑A) but has no ClinVar entry. 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 further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. The Foldetta stability prediction is inconclusive and therefore not considered evidence. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar classification. 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 | 6-33441584-G-A | 1 | 6.20e-7 | -0.836 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | 2.36 | Destabilizing | 1.43 | Ambiguous | 0.10 | Likely Benign | 0.252 | Likely Benign | -0.57 | Neutral | 0.980 | Probably Damaging | 0.947 | Probably Damaging | 3.52 | Benign | 0.44 | Tolerated | 3.50 | 9 | 0.0880 | 0.4330 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.2126T>G | L709R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. Tools with uncertain or inconclusive results are Rosetta, premPS, 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, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Overall, the majority of evidence indicates a benign impact for the variant, 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 | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -8.636 | Likely Pathogenic | 0.482 | Ambiguous | Likely Benign | 0.22 | Likely Benign | 0.0 | 0.68 | Ambiguous | 0.45 | Likely Benign | 0.62 | Ambiguous | 0.061 | Likely Benign | -1.56 | Neutral | 0.906 | Possibly Damaging | 0.314 | Benign | 3.50 | Benign | 0.44 | Tolerated | 0.1127 | 0.0488 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.2512A>G | N838D 2D  AIThe SynGAP1 missense variant N838D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, 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. 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 | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -6.035 | Likely Benign | 0.529 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -2.08 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.69 | Benign | 0.44 | Tolerated | 0.1804 | 0.2954 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2635G>T | A879S 2D  AIThe SynGAP1 missense variant A879S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, 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 | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -3.406 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.26 | Neutral | 0.580 | Possibly Damaging | 0.324 | Benign | 2.68 | Benign | 0.44 | Tolerated | 0.2469 | 0.5266 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2818G>A | G940S 2D  AIThe SynGAP1 missense variant G940S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443370‑G‑A). All available 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) is “Likely Benign.” High‑accuracy tools reinforce 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, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Uncertain | 1 | 6-33443370-G-A | 1 | 6.20e-7 | -5.451 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.45 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.77 | Benign | 0.44 | Tolerated | 3.77 | 5 | 0.2590 | 0.4907 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| 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.3091A>G | M1031V 2D  AIThe SynGAP1 missense variant M1031V is catalogued in gnomAD (ID 6‑33443643‑A‑G) 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 scores the variant as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the uniform benign predictions and the lack of any ClinVar pathogenic classification, 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 | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | 6-33443643-A-G | 7 | 4.34e-6 | -2.815 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.81 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.72 | Benign | 0.44 | Tolerated | 3.77 | 5 | 0.2305 | 0.3388 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.3401C>T | T1134I 2D  AIThe SynGAP1 missense variant T1134I 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, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, 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 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 majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -4.072 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -1.93 | Neutral | 0.453 | Possibly Damaging | 0.162 | Benign | 5.52 | Benign | 0.44 | Tolerated | 0.1071 | 0.5447 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| 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.3584T>C | V1195A 2D  AIThe SynGAP1 missense variant V1195A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default both 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 show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the balance of evidence leans toward a benign impact, 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 | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -4.291 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.421 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.60 | Benign | 0.44 | Tolerated | 0.2602 | 0.1854 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||
| c.1060G>A | A354T 2D AIThe SynGAP1 missense variant A354T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign result. No predictions or folding‑stability analyses are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -2.812 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.7 | 0.11 | Likely Benign | 0.24 | Likely Benign | -0.52 | Ambiguous | 0.097 | Likely Benign | 1.72 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.45 | Tolerated | 0.1731 | 0.6496 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1096A>G | T366A 2D  AIThe SynGAP1 missense variant T366A is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and Foldetta provides no definitive stability change. Overall, the computational evidence overwhelmingly favors a benign classification, and this is consistent with the absence of any ClinVar assertion. Therefore, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.983 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.5 | 0.86 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | 0.046 | Likely Benign | -0.94 | Neutral | 0.031 | Benign | 0.016 | Benign | 1.73 | Pathogenic | 0.45 | Tolerated | 0.4141 | 0.4785 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1226T>C | M409T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic outcome; Foldetta remains inconclusive. Overall, the majority of evidence, including the SGM‑Consensus, points to a pathogenic impact for M409T. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -9.194 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 1.41 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.95 | Ambiguous | 0.96 | Ambiguous | 0.262 | Likely Benign | -3.18 | Deleterious | 0.987 | Probably Damaging | 0.945 | Probably Damaging | 4.17 | Benign | 0.45 | Tolerated | 0.1835 | 0.2391 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1561G>A | E521K 2D  3DClick to see structure in 3D Viewer AISynGAP1 E521K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Overall, the majority of conventional tools lean toward a benign interpretation, while the high‑accuracy methods are split. Thus, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -9.596 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | -0.48 | Likely Benign | 0.2 | 0.14 | Likely Benign | -0.17 | Likely Benign | -0.10 | Likely Benign | 0.379 | Likely Benign | -3.05 | Deleterious | 0.994 | Probably Damaging | 0.994 | Probably Damaging | 3.57 | Benign | 0.45 | Tolerated | 0.2895 | 0.6513 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1597G>T | A533S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains all tools except FATHMM, which stands alone in the pathogenic group. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign effect. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.740 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.10 | Likely Benign | -0.14 | Likely Benign | 0.193 | Likely Benign | 0.33 | Neutral | 0.009 | Benign | 0.039 | Benign | -1.14 | Pathogenic | 0.45 | Tolerated | 0.2612 | 0.5334 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2125C>G | L709V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709V is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool that produced a definitive call classifies the variant as benign: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The only inconclusive results are FoldX (uncertain) and Foldetta (uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -4.406 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.0 | 0.42 | Likely Benign | 0.59 | Ambiguous | 0.03 | Likely Benign | 0.063 | Likely Benign | -0.36 | Neutral | 0.062 | Benign | 0.016 | Benign | 3.42 | Benign | 0.45 | Tolerated | 0.1162 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2161A>G | I721V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721V is not 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, 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. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the majority of reliable predictors classify the variant as 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 | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -6.730 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.0 | 1.11 | Ambiguous | 1.17 | Ambiguous | 0.48 | Likely Benign | 0.098 | Likely Benign | -0.40 | Neutral | 0.969 | Probably Damaging | 0.960 | Probably Damaging | 2.60 | Benign | 0.45 | Tolerated | 0.0976 | 0.3070 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.2262G>C | E754D 2D  AIThe SynGAP1 missense variant E754D 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 | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -2.360 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.53 | Benign | 0.45 | Tolerated | 0.1725 | 0.3983 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2262G>T | E754D 2D AIThe SynGAP1 missense variant E754D 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 trend: 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 | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -2.360 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.53 | Benign | 0.45 | Tolerated | 0.1725 | 0.3983 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>C | S816P 2D  AIThe SynGAP1 missense variant S816P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are unavailable. Overall, the preponderance of evidence points to a benign effect for S816P, and this conclusion is not in conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.662 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.26 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.66 | Benign | 0.45 | Tolerated | 0.2298 | 0.5102 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.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.2898C>A | H966Q 2D  AIThe SynGAP1 missense variant H966Q is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also 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 H966Q 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 | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | -5.662 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.66 | Neutral | 0.748 | Possibly Damaging | 0.232 | Benign | 4.06 | Benign | 0.45 | Tolerated | 0.2058 | 0.3914 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2898C>G | H966Q 2D AIThe SynGAP1 missense variant H966Q 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, 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 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 | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | -5.662 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.66 | Neutral | 0.748 | Possibly Damaging | 0.232 | Benign | 4.06 | Benign | 0.45 | Tolerated | 0.2058 | 0.3914 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2929G>T | A977S 2D AIThe SynGAP1 missense variant A977S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence indicates that A977S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.909 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.38 | Neutral | 0.965 | Probably Damaging | 0.702 | Possibly Damaging | 4.02 | Benign | 0.45 | Tolerated | 0.2820 | 0.5373 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3131C>A | P1044Q 2D  AIThe SynGAP1 missense variant P1044Q is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -4.439 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.338 | Likely Benign | 0.51 | Neutral | 0.004 | Benign | 0.015 | Benign | 5.43 | Benign | 0.45 | Tolerated | 0.1544 | 0.5591 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| 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.3493T>A | S1165T 2D  AIThe SynGAP1 missense variant S1165T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from 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 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 | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.970 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.59 | Benign | 0.45 | Tolerated | 0.1660 | 0.5579 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3589G>A | E1197K 2D AIThe SynGAP1 E1197K missense change is not reported in ClinVar and has no gnomAD entry. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, whereas AlphaMissense‑Optimized predicts it to be Pathogenic; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a benign effect, though the single high‑accuracy pathogenic prediction introduces uncertainty. The variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -5.048 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.364 | Likely Benign | -0.27 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.45 | Benign | 0.45 | Tolerated | 0.1512 | 0.5424 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| 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.943A>G | N315D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta predicts a benign stability change. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -5.667 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 1.27 | Ambiguous | 0.6 | -0.30 | Likely Benign | 0.49 | Likely Benign | 0.88 | Ambiguous | 0.229 | Likely Benign | -2.41 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.02 | Pathogenic | 0.45 | Tolerated | 0.1972 | 0.4488 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.958G>A | V320I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta remains inconclusive. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence points to a benign effect for V320I, and this conclusion does not conflict with the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Uncertain | 1 | -5.220 | Likely Benign | 0.111 | Likely Benign | Likely Benign | -0.27 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.20 | Likely Benign | 0.01 | Likely Benign | 0.027 | Likely Benign | -0.21 | Neutral | 0.198 | Benign | 0.114 | Benign | 1.77 | Pathogenic | 0.45 | Tolerated | 3.38 | 23 | 0.0514 | 0.3207 | 3 | 4 | 0.3 | 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.1279C>A | H427N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign outcome. With all available evidence pointing to a neutral effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | 1.162 | Likely Benign | 0.045 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.14 | Likely Benign | -0.48 | Likely Benign | 0.100 | Likely Benign | 1.63 | Neutral | 0.010 | Benign | 0.006 | Benign | 3.62 | Benign | 0.46 | Tolerated | 0.1507 | 0.2418 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| 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.1675T>C | C559R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C559R is not 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, FATHMM, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (six pathogenic vs five benign) lean toward a pathogenic interpretation, and this does not contradict any ClinVar status because the variant is not yet classified in ClinVar. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -9.509 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | -1.03 | Ambiguous | 0.1 | -0.38 | Likely Benign | -0.71 | Ambiguous | 0.79 | Ambiguous | 0.498 | Likely Benign | -8.58 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.48 | Benign | 0.46 | Tolerated | 0.2498 | 0.1720 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1850A>C | E617A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617A is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Rosetta and Foldetta are uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -8.704 | Likely Pathogenic | 0.769 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.89 | Ambiguous | 0.63 | Ambiguous | 0.18 | Likely Benign | 0.627 | Likely Pathogenic | -4.75 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0.3033 | 0.5317 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2204G>C | S735T 2D AIThe SynGAP1 missense variant S735T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -5.340 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.03 | Neutral | 0.980 | Probably Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.46 | Tolerated | 0.1464 | 0.5321 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.2371A>C | K791Q 2D AIThe SynGAP1 missense variant K791Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that K791Q is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.966441 | Disordered | 0.478670 | Uncertain | 0.356 | 0.896 | 0.875 | -3.418 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.09 | Neutral | 0.802 | Possibly Damaging | 0.335 | Benign | 4.17 | Benign | 0.46 | Tolerated | 0.5322 | 0.1159 | Weaken | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||
| c.2851C>G | H951D 2D AIThe SynGAP1 missense variant H951D 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated methods. 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 | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -5.901 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.186 | Likely Benign | -0.33 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.43 | Benign | 0.46 | Tolerated | 0.2851 | 0.2475 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2887C>G | H963D 2D AIThe SynGAP1 missense variant H963D 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), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic prediction comes from ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign; Foldetta results are not available. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign impact for H963D, 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 | 0.991070 | Disordered | 0.983973 | Binding | 0.325 | 0.886 | 0.750 | -12.082 | Likely Pathogenic | 0.204 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.81 | Neutral | 0.369 | Benign | 0.159 | Benign | 4.16 | Benign | 0.46 | Tolerated | 0.2482 | 0.3023 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3133G>T | A1045S 2D AIThe SynGAP1 missense variant A1045S 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, 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -3.724 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.11 | Neutral | 0.011 | Benign | 0.010 | Benign | 2.66 | Benign | 0.46 | Tolerated | 0.2648 | 0.5493 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3383G>C | G1128A 2D  AIThe SynGAP1 missense variant G1128A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.015 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -0.26 | Neutral | 0.009 | Benign | 0.008 | Benign | 4.47 | Benign | 0.46 | Tolerated | 0.3588 | 0.5252 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.344A>C | Q115P 2D  AIThe SynGAP1 missense variant Q115P 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 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -2.766 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -0.71 | Neutral | 0.990 | Probably Damaging | 0.954 | Probably Damaging | 4.08 | Benign | 0.46 | Tolerated | 0.2418 | 0.4778 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.520A>C | M174L 2D  AIThe SynGAP1 missense variant M174L is not reported 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact for M174L. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -5.839 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -0.82 | Neutral | 0.055 | Benign | 0.011 | Benign | 4.21 | Benign | 0.46 | Tolerated | 0.1335 | 0.4545 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.520A>T | M174L 2D AIThe SynGAP1 missense variant M174L is not reported 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact for M174L. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -5.839 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -0.82 | Neutral | 0.055 | Benign | 0.011 | Benign | 4.21 | Benign | 0.46 | Tolerated | 0.1335 | 0.4545 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.751A>G | K251E 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K251E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, with a small but notable benign signal. Therefore, the variant is most likely pathogenic based on 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. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -12.812 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.2 | 0.99 | Ambiguous | 0.94 | Ambiguous | 0.40 | Likely Benign | 0.571 | Likely Pathogenic | -0.54 | Neutral | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.80 | Benign | 0.46 | Tolerated | 0.3929 | 0.0860 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| c.1018G>A | A340T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A340T is reported in gnomAD (ID 6‑33437923‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all classify the change as benign or likely benign. Only two tools predict pathogenicity—polyPhen‑2 HumDiv and FATHMM—while stability‑based methods (FoldX, Rosetta, premPS, Foldetta) return uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign, and Foldetta provides no definitive stability change. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | 6-33437923-G-A | -3.286 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.84 | Ambiguous | 0.2 | 0.96 | Ambiguous | 0.90 | Ambiguous | -0.54 | Ambiguous | 0.105 | Likely Benign | 0.62 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 1.93 | Pathogenic | 0.47 | Tolerated | 3.42 | 13 | 0.1740 | 0.7297 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| 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.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.1994A>T | Y665F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, 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 Rosetta and Foldetta are uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar claim; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | -8.460 | Likely Pathogenic | 0.100 | Likely Benign | Likely Benign | 0.07 | Likely Benign | 0.1 | 1.03 | Ambiguous | 0.55 | Ambiguous | 0.38 | Likely Benign | 0.106 | Likely Benign | -1.23 | Neutral | 0.159 | Benign | 0.036 | Benign | 3.45 | Benign | 0.47 | Tolerated | 0.2277 | 0.3076 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.2017C>A | L673I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The remaining tools (FoldX, Rosetta, Foldetta, ESM1b) return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors indicate a benign effect, and there is no conflict with ClinVar status (which has no entry). Therefore, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.104692 | Uncertain | 0.545 | 0.369 | 0.000 | -7.823 | In-Between | 0.099 | Likely Benign | Likely Benign | 1.51 | Ambiguous | 0.2 | 1.89 | Ambiguous | 1.70 | Ambiguous | -0.02 | Likely Benign | 0.036 | Likely Benign | -0.14 | Neutral | 0.535 | Possibly Damaging | 0.112 | Benign | 3.37 | Benign | 0.47 | Tolerated | 0.0910 | 0.3689 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.2187C>A | N729K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2187C>G | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2188A>C | I730L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I730L is reported as “Likely Benign” in ClinVar and is not present in gnomAD. All available in‑silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.420109 | Uncertain | 0.591 | 0.619 | 0.750 | -1.681 | Likely Benign | 0.069 | Likely Benign | Likely Benign | -0.05 | Likely Benign | 0.0 | -0.31 | Likely Benign | -0.18 | Likely Benign | -0.17 | Likely Benign | 0.028 | Likely Benign | -0.63 | Neutral | 0.000 | Benign | 0.005 | Benign | 3.53 | Benign | 0.47 | Tolerated | 0.0739 | 0.2869 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2379G>C | K793N 2D  AIThe SynGAP1 missense variant K793N is catalogued in gnomAD (6‑33442931‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify it as benign, and the SGM‑Consensus score (Likely Benign) supports this view. Only AlphaMissense‑Default predicts pathogenicity. High‑accuracy assessments further reinforce the benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification. 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 K793N 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 | SH3-binding motif | 0.971072 | Disordered | 0.426071 | Uncertain | 0.344 | 0.901 | 0.875 | 6-33442931-G-C | 4 | 2.48e-6 | -5.162 | Likely Benign | 0.632 | Likely Pathogenic | Likely Benign | 0.040 | Likely Benign | 1.18 | Neutral | 0.174 | Benign | 0.135 | Benign | 4.13 | Benign | 0.47 | Tolerated | 4.07 | 3 | 0.4429 | 0.1976 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||
| c.2379G>T | K793N 2D AIThe SynGAP1 missense variant K793N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only AlphaMissense‑Default predicts a pathogenic outcome. 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 (majority vote) 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 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 | SH3-binding motif | 0.971072 | Disordered | 0.426071 | Uncertain | 0.344 | 0.901 | 0.875 | -5.162 | Likely Benign | 0.632 | Likely Pathogenic | Likely Benign | 0.040 | Likely Benign | 1.18 | Neutral | 0.174 | Benign | 0.135 | Benign | 4.13 | Benign | 0.47 | Tolerated | 4.07 | 3 | 0.4429 | 0.1976 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||
| c.2471G>C | S824T 2D AIThe SynGAP1 missense variant S824T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -4.135 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -0.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.62 | Benign | 0.47 | Tolerated | 0.1760 | 0.6525 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2483C>G | T828R 2D  AIThe SynGAP1 missense variant T828R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T828R, 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 | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -4.887 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.38 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.47 | Tolerated | 0.0815 | 0.2530 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2981A>G | K994R 2D  AIThe SynGAP1 missense variant K994R 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 | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -1.990 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.02 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.21 | Benign | 0.47 | Tolerated | 0.5064 | 0.1657 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3268A>G | N1090D 2D AIThe SynGAP1 missense variant N1090D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.354 | Likely Benign | 0.827 | Likely Pathogenic | Ambiguous | 0.066 | Likely Benign | -1.39 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 0.47 | Tolerated | 0.1994 | 0.4375 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3901C>A | P1301T 2D  AIThe SynGAP1 missense variant P1301T is reported in gnomAD (ID 6‑33451775‑C‑A) 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, so the pathogenic group is empty. High‑accuracy assessments reinforce this benign prediction: 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 consensus of all available predictions, 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-A | 1 | 6.20e-7 | -4.945 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.34 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.87 | Benign | 0.47 | Tolerated | 3.77 | 5 | 0.1255 | 0.3312 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.1016A>G | K339R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No predictions or stability results are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -5.773 | Likely Benign | 0.120 | Likely Benign | Likely Benign | -0.15 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.16 | Likely Benign | 0.08 | Likely Benign | 0.134 | Likely Benign | -2.05 | Neutral | 0.046 | Benign | 0.040 | Benign | 1.94 | Pathogenic | 0.48 | Tolerated | 0.4197 | 0.0976 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.1442A>T | H481L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H481L missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools (seven benign vs five pathogenic) lean toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign, though a subset of high‑accuracy predictors suggest pathogenicity, indicating some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -9.097 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.58 | Ambiguous | 0.1 | 0.15 | Likely Benign | -0.22 | Likely Benign | 0.29 | Likely Benign | 0.349 | Likely Benign | -5.91 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.41 | Benign | 0.48 | Tolerated | 0.0661 | 0.4678 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1585A>C | I529L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529L is listed in gnomAD (variant ID 6‑33438828‑A‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. 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; the SGM‑Consensus (majority vote) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No prediction or folding 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 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 | 6-33438828-A-C | 1 | 6.20e-7 | 0.920 | Likely Benign | 0.066 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.0 | -0.11 | Likely Benign | -0.12 | Likely Benign | -0.21 | Likely Benign | 0.309 | Likely Benign | 0.00 | Neutral | 0.001 | Benign | 0.022 | Benign | -1.24 | Pathogenic | 0.48 | Tolerated | 3.37 | 35 | 0.0819 | 0.3789 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||
| c.1654T>C | C552R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) yields an uncertain result, which is treated as unavailable evidence. Overall, the preponderance of predictions supports a pathogenic classification, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -14.315 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.18 | Ambiguous | 0.1 | -0.51 | Ambiguous | -0.85 | Ambiguous | 1.10 | Destabilizing | 0.809 | Likely Pathogenic | -9.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.19 | Pathogenic | 0.48 | Tolerated | 0.1449 | 0.1366 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1849G>A | E617K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617K is not reported in ClinVar but is present in gnomAD (6‑33440901‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. A third set of methods (Foldetta, AlphaMissense‑Optimized, Rosetta) yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect for E617K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | 6-33440901-G-A | 1 | 6.20e-7 | -10.702 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.37 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.78 | Ambiguous | 0.17 | Likely Benign | 0.534 | Likely Pathogenic | -3.32 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | -1.34 | Pathogenic | 0.48 | Tolerated | 3.37 | 35 | 0.1981 | 0.6282 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1993T>C | Y665H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665H is not reported in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID: 6‑33441252‑T‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain. Overall, the majority of predictions (7 benign vs. 4 pathogenic) and the high‑accuracy consensus support a benign classification. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | 6-33441252-T-C | 2 | 1.24e-6 | -9.303 | Likely Pathogenic | 0.389 | Ambiguous | Likely Benign | 0.85 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.57 | Ambiguous | 1.12 | Destabilizing | 0.129 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.45 | Benign | 0.48 | Tolerated | 3.38 | 28 | 0.2122 | 0.0513 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.2126T>A | L709Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the 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 | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -5.758 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.27 | Likely Benign | 0.18 | Likely Benign | 0.033 | Likely Benign | -0.78 | Neutral | 0.998 | Probably Damaging | 0.923 | Probably Damaging | 3.52 | Benign | 0.48 | Tolerated | 0.0838 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2386C>T | P796S 2D  AIThe SynGAP1 missense variant P796S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) reports likely benign. Foldetta results are not available for this variant. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -5.382 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.05 | Neutral | 0.174 | Benign | 0.091 | Benign | 4.28 | Benign | 0.48 | Tolerated | 0.3560 | 0.4171 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2401G>A | G801S 2D AIThe SynGAP1 missense variant G801S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors classify the change as benign: SGM‑Consensus (Likely 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 benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the evidence strongly supports 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | Uncertain | 1 | -3.665 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.41 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.76 | Benign | 0.48 | Tolerated | 4.32 | 2 | 0.2325 | 0.4755 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2581T>G | S861A 2D AIThe SynGAP1 missense variant S861A 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 results are unavailable. Based on the collective predictions, 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 | 0.557691 | Disordered | 0.540903 | Binding | 0.285 | 0.797 | 0.250 | -5.059 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.409 | Benign | 0.172 | Benign | 4.08 | Benign | 0.48 | Tolerated | 0.4541 | 0.5401 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>A | P954T 2D AIThe SynGAP1 missense variant P954T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.657 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.77 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.79 | Benign | 0.48 | Tolerated | 0.1860 | 0.6324 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2932C>T | P978S 2D AIThe SynGAP1 missense variant P978S is listed in ClinVar (ID 3379672.0) with an “Uncertain” clinical significance 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 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign effect, which 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 | 0.819762 | Disordered | 0.975775 | Binding | 0.425 | 0.892 | 0.625 | Uncertain | 1 | -3.913 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.07 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 4.22 | Benign | 0.48 | Tolerated | 0.3428 | 0.6001 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||
| c.3199C>T | P1067S 2D AIThe SynGAP1 missense variant P1067S 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. Based on the collective predictions, 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.673 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.43 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.91 | Benign | 0.48 | Tolerated | 0.3086 | 0.5753 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3445C>T | P1149S 2D AIThe SynGAP1 missense variant P1149S 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 variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -2.650 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.14 | Neutral | 0.068 | Benign | 0.065 | Benign | 3.18 | Benign | 0.48 | Tolerated | 0.3460 | 0.4826 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3481A>C | M1161L 2D AIThe SynGAP1 missense variant M1161L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Consequently, the available computational evidence is conflicting, with an equal number of benign and pathogenic predictions and no definitive high‑accuracy support. The variant is most likely of uncertain significance; this lack of consensus is consistent with its absence from ClinVar and gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.129 | Likely Benign | 0.862 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.59 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.38 | Pathogenic | 0.48 | Tolerated | 0.1614 | 0.4244 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3481A>T | M1161L 2D AISynGAP1 missense variant M1161L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall computational evidence does not strongly favor either outcome. The variant is most likely inconclusive in pathogenicity prediction, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.129 | Likely Benign | 0.862 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.59 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.38 | Pathogenic | 0.48 | Tolerated | 0.1614 | 0.4244 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3919C>T | P1307S 2D AIThe SynGAP1 missense variant P1307S 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, derived from a 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 | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -3.700 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.45 | Neutral | 0.239 | Benign | 0.157 | Benign | 3.09 | Benign | 0.48 | Tolerated | 0.3652 | 0.4846 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| 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.1732G>A | E578K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E578K is not 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, and SIFT, whereas polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default predict a pathogenic outcome. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic, AlphaMissense‑Optimized remains Uncertain, and Foldetta predicts a benign effect. Overall, the majority of tools (seven benign vs. five pathogenic) suggest a benign impact, and this assessment does not contradict the absence of ClinVar evidence. Thus, the variant is most likely benign based on the current predictions, with no conflicting ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.020971 | Uncertain | 0.902 | 0.240 | 0.000 | -13.391 | Likely Pathogenic | 0.870 | Likely Pathogenic | Ambiguous | 0.07 | Likely Benign | 0.1 | -0.19 | Likely Benign | -0.06 | Likely Benign | -0.27 | Likely Benign | 0.450 | Likely Benign | -1.65 | Neutral | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.30 | Pathogenic | 0.49 | Tolerated | 0.1954 | 0.5480 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1831A>G | M611V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields an inconclusive result (two benign, two pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect, so its result is treated as unavailable. Overall, the balance of evidence leans toward a benign impact, 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. | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.057 | Likely Pathogenic | 0.176 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.4 | 1.56 | Ambiguous | 1.49 | Ambiguous | 0.66 | Ambiguous | 0.315 | Likely Benign | -2.06 | Neutral | 0.960 | Probably Damaging | 0.474 | Possibly Damaging | -1.04 | Pathogenic | 0.49 | Tolerated | 0.2324 | 0.2721 | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||
| c.2927T>C | F976S 2D  AIThe SynGAP1 missense variant F976S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Based on the collective 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -2.393 | Likely Benign | 0.432 | Ambiguous | Likely Benign | 0.217 | Likely Benign | -0.73 | Neutral | 0.292 | Benign | 0.102 | Benign | 4.16 | Benign | 0.49 | Tolerated | 0.4432 | 0.1134 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2959G>A | D987N 2D  AIThe SynGAP1 D987N missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -5.035 | Likely Benign | 0.698 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.42 | Neutral | 0.943 | Possibly Damaging | 0.755 | Possibly Damaging | 2.41 | Pathogenic | 0.49 | Tolerated | 0.1331 | 0.7427 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3010C>T | H1004Y 2D  AIThe SynGAP1 missense variant H1004Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.196 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -1.67 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.72 | Benign | 0.49 | Tolerated | 0.1175 | 0.5143 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3167G>C | G1056A 2D AIThe SynGAP1 missense variant G1056A is not 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), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, 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 consensus (2 benign vs. 1 pathogenic, with one uncertain). 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 because no ClinVar entry exists. 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 | -7.458 | In-Between | 0.086 | Likely Benign | Likely Benign | 0.325 | Likely Benign | -0.25 | Neutral | 0.264 | Benign | 0.097 | Benign | 1.85 | Pathogenic | 0.49 | Tolerated | 0.3325 | 0.4957 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3178G>A | G1060S 2D AIThe SynGAP1 missense variant G1060S is listed in ClinVar with an uncertain significance (ClinVar ID 1512003.0) and is present in gnomAD (variant ID 6‑33443730‑G‑A). 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 benign view: AlphaMissense‑Optimized reports 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, did not provide a result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | Uncertain | 1 | 6-33443730-G-A | -4.759 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.376 | Likely Benign | -0.08 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.69 | Benign | 0.49 | Tolerated | 4.32 | 2 | 0.2468 | 0.5311 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3616A>C | K1206Q 2D AIThe SynGAP1 K1206Q missense change is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta data are unavailable. Consequently, the evidence is evenly split between benign and pathogenic interpretations. The variant therefore falls into a category of uncertain significance, with no conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -8.654 | Likely Pathogenic | 0.817 | Likely Pathogenic | Ambiguous | 0.130 | Likely Benign | -0.92 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.49 | Tolerated | 0.3829 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.1441C>G | H481D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic signal: the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Uncertain results from AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect for H481D, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.822 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | -0.09 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.23 | Likely Benign | 0.70 | Ambiguous | 0.273 | Likely Benign | -5.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.50 | Tolerated | 0.2109 | 0.1058 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.2372A>G | K791R 2D AIThe SynGAP1 missense variant K791R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also 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 K791R, 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 | 0.966441 | Disordered | 0.478670 | Uncertain | 0.356 | 0.896 | 0.875 | -2.359 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -0.96 | Neutral | 0.802 | Possibly Damaging | 0.249 | Benign | 4.14 | Benign | 0.50 | Tolerated | 0.5520 | 0.1223 | Weaken | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||
| c.2402G>C | G801A 2D AIThe SynGAP1 missense variant G801A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. **Overall, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -3.747 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.61 | Neutral | 0.025 | Benign | 0.034 | Benign | 2.83 | Benign | 0.50 | Tolerated | 0.3458 | 0.4681 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2470A>G | S824G 2D  AIThe SynGAP1 missense variant S824G is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443022‑A‑G). 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. 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, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Based on the preponderance of benign predictions and the consensus from high‑accuracy tools, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | 6-33443022-A-G | 1 | 6.20e-7 | -5.476 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.60 | Benign | 0.50 | Tolerated | 3.77 | 5 | 0.2880 | 0.5437 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2513A>G | N838S 2D  AIThe SynGAP1 missense variant at residue N838S is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). 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 classifiers (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 unavailable. Overall, the majority of evidence supports a benign classification, and this is not in conflict with ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -3.748 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -1.24 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.83 | Benign | 0.50 | Tolerated | 0.3552 | 0.5485 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2869C>A | H957N 2D AIThe SynGAP1 missense variant H957N 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 substitution as benign. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the 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. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.804 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.45 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.45 | Pathogenic | 0.50 | Tolerated | 0.2343 | 0.3788 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3011A>G | H1004R 2D  AIThe SynGAP1 missense variant H1004R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.316 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.198 | Likely Benign | -1.88 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.77 | Benign | 0.50 | Tolerated | 0.2097 | 0.3132 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3040G>A | G1014S 2D AIThe SynGAP1 missense variant G1014S 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the 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 | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -3.219 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.60 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.95 | Benign | 0.50 | Tolerated | 0.2677 | 0.5408 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3080A>G | N1027S 2D AIThe SynGAP1 missense variant N1027S 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 suggest that 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -2.443 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.35 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.77 | Benign | 0.50 | Tolerated | 0.3540 | 0.6874 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3338G>C | G1113A 2D AIThe SynGAP1 missense variant G1113A 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 | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.714 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.15 | Neutral | 0.798 | Possibly Damaging | 0.433 | Benign | 2.58 | Benign | 0.50 | Tolerated | 0.3444 | 0.5342 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3394T>A | S1132T 2D AIThe SynGAP1 missense variant S1132T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -3.700 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -0.71 | Neutral | 0.011 | Benign | 0.017 | Benign | 5.45 | Benign | 0.50 | Tolerated | 0.1552 | 0.6309 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3700C>G | L1234V 2D AIThe SynGAP1 missense variant L1234V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools, AlphaMissense‑Default and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result. Overall, the balance of evidence leans toward a benign classification, and this assessment 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. | Coiled-coil | 0.599170 | Disordered | 0.575096 | Binding | 0.844 | 0.527 | 0.125 | -7.863 | In-Between | 0.402 | Ambiguous | Likely Benign | 0.090 | Likely Benign | -1.80 | Neutral | 0.898 | Possibly Damaging | 0.602 | Possibly Damaging | 1.54 | Pathogenic | 0.50 | Tolerated | 0.1314 | 0.2918 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1018G>T | A340S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340S is reported in gnomAD (variant ID 6‑33437923‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | 6-33437923-G-T | 1 | 6.20e-7 | -0.705 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.21 | Likely Benign | -0.46 | Likely Benign | 0.083 | Likely Benign | 1.62 | Neutral | 0.007 | Benign | 0.008 | Benign | 1.93 | Pathogenic | 0.51 | Tolerated | 3.42 | 13 | 0.2852 | 0.6309 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||
| c.1288A>G | M430V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated changes. Only polyPhen‑2 HumDiv flags it as pathogenic, while the SGM‑Consensus score is Likely Benign. Stability‑based methods are inconclusive: FoldX and premPS return Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -3.555 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 1.48 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.63 | Ambiguous | 0.87 | Ambiguous | 0.103 | Likely Benign | -1.35 | Neutral | 0.918 | Possibly Damaging | 0.185 | Benign | 3.53 | Benign | 0.51 | Tolerated | 0.3397 | 0.4953 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1443C>A | H481Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H481Q 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, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence leans toward a benign effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.524 | Likely Pathogenic | 0.663 | Likely Pathogenic | Likely Benign | -0.41 | Likely Benign | 0.1 | 0.31 | Likely Benign | -0.05 | Likely Benign | 0.32 | Likely Benign | 0.243 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.55 | Benign | 0.51 | Tolerated | 0.1052 | 0.2797 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1443C>G | H481Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H481Q 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, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence leans toward a benign effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.524 | Likely Pathogenic | 0.663 | Likely Pathogenic | Likely Benign | -0.41 | Likely Benign | 0.1 | 0.31 | Likely Benign | -0.05 | Likely Benign | 0.32 | Likely Benign | 0.243 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.55 | Benign | 0.51 | Tolerated | 0.1052 | 0.2797 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| 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.2168C>A | T723K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence supports a benign classification for T723K, 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 | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | -4.624 | Likely Benign | 0.482 | Ambiguous | Likely Benign | -0.77 | Ambiguous | 0.1 | -0.04 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | 0.121 | Likely Benign | -1.40 | Neutral | 0.674 | Possibly Damaging | 0.118 | Benign | 3.46 | Benign | 0.51 | Tolerated | 0.0924 | 0.2798 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.2213G>C | S738T 2D AIThe SynGAP1 missense variant S738T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -3.926 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.68 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.73 | Benign | 0.51 | Tolerated | 0.1336 | 0.4227 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.2594C>G | A865G 2D  AIThe SynGAP1 missense variant A865G 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 results are unavailable. Based on the collective predictions, 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 | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -3.412 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -0.74 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.69 | Benign | 0.51 | Tolerated | 0.2344 | 0.4683 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2827G>A | G943S 2D AIThe SynGAP1 missense variant G943S 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. 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 | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -5.785 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.295 | Likely Benign | 0.34 | Neutral | 0.059 | Benign | 0.039 | Benign | 2.88 | Benign | 0.51 | Tolerated | 0.2482 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2906G>C | G969A 2D AIThe SynGAP1 missense variant G969A 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, so the pathogenic‑prediction group is empty. High‑accuracy assessments corroborate this benign consensus: 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 interpretation. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.693 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.36 | Neutral | 0.393 | Benign | 0.096 | Benign | 4.25 | Benign | 0.51 | Tolerated | 0.3414 | 0.5096 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3185G>C | G1062A 2D AIThe SynGAP1 missense variant G1062A 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 benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.124 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.350 | Likely Benign | 0.20 | Neutral | 0.059 | Benign | 0.028 | Benign | 4.20 | Benign | 0.51 | Tolerated | 0.3305 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3456G>C | E1152D 2D AIThe SynGAP1 missense variant E1152D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to the variant being 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 | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -3.488 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.171 | Likely Benign | -0.45 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.76 | Benign | 0.51 | Tolerated | 0.2151 | 0.4770 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3456G>T | E1152D 2D AIThe SynGAP1 missense variant E1152D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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, 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 the variant being 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 | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -3.488 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.171 | Likely Benign | -0.45 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.76 | Benign | 0.51 | Tolerated | 0.2151 | 0.4770 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3548A>C | Y1183S 2D  AIThe SynGAP1 missense variant Y1183S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, SIFT, ESM1b, FATHMM) and pathogenic predictions (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for Y1183S, 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 | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.514 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | -1.57 | Neutral | 0.951 | Possibly Damaging | 0.619 | Possibly Damaging | 2.86 | Benign | 0.51 | Tolerated | 0.5346 | 0.1096 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.3550T>G | S1184A 2D AIThe SynGAP1 missense variant S1184A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools are divided: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the 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 | Coiled-coil | 0.648219 | Disordered | 0.514669 | Binding | 0.624 | 0.642 | 0.500 | -3.753 | Likely Benign | 0.595 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -1.11 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.73 | Benign | 0.51 | Tolerated | 0.4093 | 0.3850 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3603G>C | E1201D 2D AIThe SynGAP1 missense variant E1201D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, and SIFT, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic classification. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -8.727 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -1.55 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.66 | Pathogenic | 0.51 | Tolerated | 0.1341 | 0.3335 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3603G>T | E1201D 2D AIThe SynGAP1 missense variant E1201D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, and SIFT, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic classification. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -8.727 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -1.55 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.66 | Pathogenic | 0.51 | Tolerated | 0.1341 | 0.3335 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| 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.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.474G>C | Q158H 2D  AIThe SynGAP1 missense variant Q158H 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 is not contradicted by any ClinVar status. 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 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 0.1403 | 0.3774 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.474G>T | Q158H 2D AIThe SynGAP1 missense variant Q158H 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 is not contradicted by any ClinVar status. 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 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 0.1403 | 0.3774 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.1142G>C | G381A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381A is reported in gnomAD (variant ID 6-33438047‑G‑C) but has no ClinVar entry. Functional prediction tools fall into two groups: benign predictions come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar; pathogenic predictions come from REVEL, FoldX, Rosetta, polyPhen‑2 HumDiv, FATHMM, and the SGM‑Consensus score. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Overall, the majority of tools suggest a benign effect, and the high‑accuracy consensus leans toward benign, though Foldetta’s pathogenic signal introduces uncertainty. The variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438047-G-C | 1 | 6.23e-7 | -6.266 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 3.97 | Destabilizing | 0.7 | 2.05 | Destabilizing | 3.01 | Destabilizing | 0.06 | Likely Benign | 0.507 | Likely Pathogenic | -0.63 | Neutral | 0.718 | Possibly Damaging | 0.332 | Benign | 1.33 | Pathogenic | 0.52 | Tolerated | 4.32 | 9 | 0.3809 | 0.4770 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||
| c.1721T>G | L574R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L574R is not 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, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. Two tools remain inconclusive: Rosetta (Uncertain) and AlphaMissense‑Default (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of individual predictors (seven benign vs. three pathogenic) support a benign classification, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | -8.702 | Likely Pathogenic | 0.563 | Ambiguous | Likely Benign | 0.04 | Likely Benign | 0.2 | 0.88 | Ambiguous | 0.46 | Likely Benign | -0.12 | Likely Benign | 0.322 | Likely Benign | 0.30 | Neutral | 0.907 | Possibly Damaging | 0.292 | Benign | -1.22 | Pathogenic | 0.52 | Tolerated | 0.1419 | 0.0530 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.1807A>C | M603L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M603L 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 FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and 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 benign. Overall, more evidence supports a benign effect (six benign versus five pathogenic predictions, with two uncertain). Thus, 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. | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -7.134 | In-Between | 0.590 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.86 | Ambiguous | 0.45 | Likely Benign | -0.18 | Likely Benign | 0.548 | Likely Pathogenic | -2.16 | Neutral | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -0.98 | Pathogenic | 0.52 | Tolerated | 0.1345 | 0.3227 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||
| c.1807A>T | M603L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M603L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Rosetta and ESM1b give uncertain results. 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 lean toward a benign interpretation, but the SGM Consensus indicates pathogenicity, leaving the variant’s clinical significance uncertain. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for M603L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -7.134 | In-Between | 0.590 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.86 | Ambiguous | 0.45 | Likely Benign | -0.18 | Likely Benign | 0.548 | Likely Pathogenic | -2.16 | Neutral | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -0.98 | Pathogenic | 0.52 | Tolerated | 0.1345 | 0.3227 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||
| c.2116G>A | E706K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the change as benign. In contrast, ESM1b and AlphaMissense‑Default predict a pathogenic impact. Tools that return uncertain results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—do not provide decisive evidence. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign calls). High‑accuracy assessments are likewise ambiguous: AlphaMissense‑Optimized is uncertain, Foldetta is uncertain, and the SGM Consensus remains inconclusive. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | Uncertain | 1 | -10.519 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 1.17 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.84 | Ambiguous | 0.08 | Likely Benign | 0.080 | Likely Benign | -1.51 | Neutral | 0.345 | Benign | 0.028 | Benign | 4.15 | Benign | 0.52 | Tolerated | 3.47 | 10 | 0.2065 | 0.4511 | 0 | 1 | -0.4 | -0.94 | 187.1 | 49.2 | 0.0 | 0.0 | 0.4 | 0.1 | X | Uncertain | The carboxylate side chain of Glu706, located at the end and outer surface of an α-helix (res. Thr704-Gly712), forms a salt bridge with Lys710 and a hydrogen bond with its own backbone amino group at the helix end in the WT simulations. Although Lys706 is unable to make these transient interactions in the variant simulations, there is no apparent negative effect on the protein structure due to the residue swap. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||||||||
| 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.2593G>T | A865S 2D AIThe SynGAP1 missense variant A865S is reported as “Likely Benign” in SGM‑Consensus and has no ClinVar entry or gnomAD allele. 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 in the dataset predicts 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 benign. Foldetta results are not available. Overall, 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 | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -3.102 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.20 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.78 | Benign | 0.52 | Tolerated | 0.2314 | 0.4876 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2848G>A | G950S 2D AIThe SynGAP1 missense variant G950S is not 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, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). 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. 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 | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -5.286 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.288 | Likely Benign | 0.46 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.32 | Pathogenic | 0.52 | Tolerated | 0.2459 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3133G>A | A1045T 2D AIThe SynGAP1 missense variant A1045T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -4.531 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.03 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.68 | Benign | 0.52 | Tolerated | 0.1857 | 0.6682 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3169A>G | S1057G 2D AIThe SynGAP1 missense variant S1057G is reported in gnomAD (ID 6‑33443721‑A‑G) but 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 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 current predictions, 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 | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-G | 1 | 7.20e-7 | -1.005 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.47 | Neutral | 0.421 | Benign | 0.111 | Benign | 5.76 | Benign | 0.52 | Tolerated | 3.77 | 5 | 0.2654 | 0.4846 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.328G>A | V110I 2D AIThe SynGAP1 missense variant V110I 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 | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -4.409 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.10 | Neutral | 0.012 | Benign | 0.006 | Benign | 4.26 | Benign | 0.52 | Tolerated | 0.0875 | 0.4485 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.367G>A | A123T 2D AIThe SynGAP1 missense variant A123T is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the variant is most likely benign, and this 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 | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -3.999 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.59 | Neutral | 0.004 | Benign | 0.001 | Benign | 4.29 | Benign | 0.52 | Tolerated | 0.1912 | 0.7109 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.653T>A | F218Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. The high‑accuracy folding‑stability tool Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign impact. No tool predicts pathogenicity, and no contradictory evidence exists in ClinVar. **Based on the consensus of all predictions, the variant is most likely benign, and this assessment does not conflict with ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -3.596 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.40 | Likely Benign | -0.07 | Likely Benign | -0.44 | Likely Benign | 0.229 | Likely Benign | 0.63 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.95 | Benign | 0.52 | Tolerated | 0.1532 | 0.2725 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1189T>A | C397S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while Rosetta remains uncertain. When predictions are grouped, the benign category contains all available evidence and the pathogenic category is empty. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Consequently, 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 | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -2.324 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.48 | Likely Benign | 0.43 | Likely Benign | 0.174 | Likely Benign | -0.01 | Neutral | 0.276 | Benign | 0.066 | Benign | 4.68 | Benign | 0.53 | Tolerated | 0.5221 | 0.2474 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.1190G>C | C397S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). In silico prediction tools that assess pathogenicity largely agree on a benign outcome: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool predicts pathogenicity; Rosetta’s assessment is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Consequently, the variant is most likely benign based on the collective predictions, 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 | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -2.324 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.48 | Likely Benign | 0.43 | Likely Benign | 0.253 | Likely Benign | -0.01 | Neutral | 0.276 | Benign | 0.066 | Benign | 4.68 | Benign | 0.53 | Tolerated | 0.5221 | 0.2474 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| 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.1426T>G | F476V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 F476V variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that agree on a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and Foldetta. Tools with uncertain or mixed outputs are Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic impact. Overall, the majority of evidence points toward a pathogenic effect. The variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.329 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 3.01 | Destabilizing | 0.2 | 1.90 | Ambiguous | 2.46 | Destabilizing | 0.64 | Ambiguous | 0.353 | Likely Benign | -1.63 | Neutral | 0.996 | Probably Damaging | 0.993 | Probably Damaging | 3.49 | Benign | 0.53 | Tolerated | 0.1478 | 0.2251 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||
| c.1442A>G | H481R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H481R is not listed in ClinVar and has no reported allele in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, premPS, and Rosetta. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.753 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | -0.45 | Likely Benign | 0.1 | 0.68 | Ambiguous | 0.12 | Likely Benign | 0.59 | Ambiguous | 0.252 | Likely Benign | -4.48 | Deleterious | 0.983 | Probably Damaging | 0.977 | Probably Damaging | 3.47 | Benign | 0.53 | Tolerated | 0.1515 | 0.1690 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| 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.2013C>A | D671E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign. The only inconclusive result is AlphaMissense‑Default, which is listed as uncertain; all other high‑accuracy predictors support a benign outcome. In particular, AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -3.657 | Likely Benign | 0.371 | Ambiguous | Likely Benign | -0.17 | Likely Benign | 0.1 | 0.22 | Likely Benign | 0.03 | Likely Benign | 0.03 | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.013 | Benign | 0.009 | Benign | 3.47 | Benign | 0.53 | Tolerated | 0.1520 | 0.6388 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2013C>G | D671E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. With all available evidence pointing to a benign effect and no ClinVar record to contradict this, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -3.657 | Likely Benign | 0.371 | Ambiguous | Likely Benign | -0.17 | Likely Benign | 0.1 | 0.22 | Likely Benign | 0.03 | Likely Benign | 0.03 | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.013 | Benign | 0.009 | Benign | 3.47 | Benign | 0.53 | Tolerated | 0.1520 | 0.6388 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2335A>G | S779G 2D AIThe SynGAP1 missense variant S779G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.304 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.38 | Neutral | 0.393 | Benign | 0.324 | Benign | 2.65 | Benign | 0.53 | Tolerated | 0.2894 | 0.5087 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2799C>A | H933Q 2D AIThe SynGAP1 missense variant H933Q has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign (two benign versus one pathogenic vote). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -3.042 | Likely Benign | 0.410 | Ambiguous | Likely Benign | 0.211 | Likely Benign | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.54 | Benign | 0.53 | Tolerated | 0.1654 | 0.3938 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2799C>G | H933Q 2D AIThe SynGAP1 H933Q 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction between the predictions and ClinVar status. 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 | -3.042 | Likely Benign | 0.410 | Ambiguous | Likely Benign | 0.210 | Likely Benign | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.54 | Benign | 0.53 | Tolerated | 0.1654 | 0.3938 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2926T>C | F976L 2D  AIThe SynGAP1 missense variant F976L is not reported 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 the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as “Likely Benign.” In contrast, AlphaMissense‑Default predicts a pathogenic effect, while AlphaMissense‑Optimized is uncertain. No Foldetta (FoldX‑MD/ Rosetta) stability result is available, so it does not contribute to the assessment. Overall, the majority of high‑confidence predictors indicate 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. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 0.2829 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.2928T>A | F976L 2D AIThe SynGAP1 missense variant F976L is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443480‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote from 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 preponderance of evidence from high‑accuracy predictors and consensus analysis indicates that F976L is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | 6-33443480-T-A | 2 | 1.24e-6 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 0.2829 | 0.3082 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.2928T>G | F976L 2D AIThe SynGAP1 missense variant F976L is listed in ClinVar (ID 624245.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome. The high‑accuracy consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized is inconclusive, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. 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 predictions do not contradict the current ClinVar status. 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 | Uncertain | 1 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 0.2829 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.3052A>G | T1018A 2D AIThe SynGAP1 missense variant T1018A is not 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, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic 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, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -3.289 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.34 | Pathogenic | 0.53 | Tolerated | 0.3859 | 0.3362 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3090C>A | H1030Q 2D AIThe SynGAP1 missense variant H1030Q 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 0.1538 | 0.4001 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3090C>G | H1030Q 2D AIThe SynGAP1 missense variant H1030Q 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 0.1538 | 0.4001 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3587A>G | K1196R 2D AIThe SynGAP1 missense variant K1196R 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 neutral effect, and the SGM‑Consensus score is “Likely Benign.” No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion 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 | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -2.077 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.78 | Neutral | 0.031 | Benign | 0.047 | Benign | 5.39 | Benign | 0.53 | Tolerated | 0.3970 | 0.0721 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.616A>G | I206V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. 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 | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -5.709 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.73 | Ambiguous | 0.40 | Likely Benign | 0.051 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.27 | Benign | 0.53 | Tolerated | 0.0833 | 0.2920 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.944A>C | N315T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315T is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of individual predictors (six benign vs. four pathogenic) and the Foldetta result support a benign classification, while the SGM Consensus suggests pathogenicity. Thus, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -7.071 | In-Between | 0.211 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | -0.36 | Likely Benign | -0.03 | Likely Benign | 0.62 | Ambiguous | 0.333 | Likely Benign | -2.91 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.95 | Pathogenic | 0.53 | Tolerated | 0.1471 | 0.8068 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.1328G>C | G443A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -0.332 | Likely Benign | 0.101 | Likely Benign | Likely Benign | -0.59 | Ambiguous | 0.1 | -1.61 | Ambiguous | -1.10 | Ambiguous | -0.52 | Ambiguous | 0.033 | Likely Benign | -1.04 | Neutral | 0.022 | Benign | 0.011 | Benign | 3.41 | Benign | 0.54 | Tolerated | 0.3539 | 0.3192 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2096T>C | V699A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V699A has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while premPS, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict a pathogenic impact. Tools with inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Benign, and the high‑accuracy AlphaMissense‑Optimized also reports Benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | -6.017 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 1.37 | Ambiguous | 0.0 | 1.30 | Ambiguous | 1.34 | Ambiguous | 1.21 | Destabilizing | 0.236 | Likely Benign | -2.39 | Neutral | 0.861 | Possibly Damaging | 0.625 | Possibly Damaging | 3.42 | Benign | 0.54 | Tolerated | 0.2450 | 0.2124 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.2389C>G | P797A 2D  AIThe SynGAP1 missense variant P797A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence indicates that P797A is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.926919 | Disordered | 0.449970 | Uncertain | 0.561 | 0.902 | 0.875 | -5.548 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -0.33 | Neutral | 0.649 | Possibly Damaging | 0.535 | Possibly Damaging | 4.25 | Benign | 0.54 | Tolerated | 0.3704 | 0.4832 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2626T>G | S876A 2D AIThe SynGAP1 missense variant S876A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -4.228 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.43 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.63 | Benign | 0.54 | Tolerated | 0.4495 | 0.5889 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3043A>G | T1015A 2D AIThe SynGAP1 missense variant T1015A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. 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 benign, 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -2.615 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.07 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.73 | Benign | 0.54 | Tolerated | 0.3960 | 0.3949 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3508A>G | S1170G 2D AIThe SynGAP1 missense variant S1170G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, 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 | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | Uncertain | 1 | -4.288 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -0.81 | Neutral | 0.241 | Benign | 0.229 | Benign | 5.31 | Benign | 0.54 | Tolerated | 4.32 | 4 | 0.2705 | 0.4558 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.3665G>A | R1222K 2D  AIThe SynGAP1 missense variant R1222K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the change as benign, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the SGM‑Consensus designation but contradicts the benign calls from several other predictors. Thus, based on the current computational predictions, the variant is most likely pathogenic, and this assessment aligns with the lack of ClinVar reporting rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -9.148 | Likely Pathogenic | 0.689 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | -2.05 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.57 | Pathogenic | 0.54 | Tolerated | 0.3714 | 0.2611 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.842A>T | Y281F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No evidence from the uncertain FoldX result is considered. Overall, the consensus of high‑confidence tools points to a benign classification, which is consistent with the absence of ClinVar evidence and gnomAD data. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no reported pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -3.991 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.2 | -0.26 | Likely Benign | 0.25 | Likely Benign | -0.37 | Likely Benign | 0.372 | Likely Benign | -0.32 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.17 | Pathogenic | 0.54 | Tolerated | 0.2380 | 0.3885 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.913A>T | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.135 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.914C>G | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.104 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.945C>A | N315K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and Foldetta. Tools that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No other high‑accuracy tool provides a conclusive result. Overall, the majority of predictions (seven pathogenic vs. five benign, with two uncertain) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -10.380 | Likely Pathogenic | 0.872 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.03 | Likely Benign | 0.87 | Ambiguous | 0.340 | Likely Benign | -3.27 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.98 | Pathogenic | 0.54 | Tolerated | 0.2268 | 0.6436 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.945C>G | N315K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and Foldetta. Tools that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence (seven pathogenic vs. five benign, with two uncertain) points to a pathogenic impact. Thus, 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 | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -10.380 | Likely Pathogenic | 0.872 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.03 | Likely Benign | 0.87 | Ambiguous | 0.340 | Likely Benign | -3.27 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.98 | Pathogenic | 0.54 | Tolerated | 0.2268 | 0.6436 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| 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.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.1108G>C | G370R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, FoldX, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the balance of evidence leans toward pathogenicity, with two of the three high‑accuracy tools supporting this view. The variant is most likely pathogenic, 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 Pathogenic | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -8.375 | Likely Pathogenic | 0.731 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 3.7 | 1.72 | Ambiguous | 2.67 | Destabilizing | 0.22 | Likely Benign | 0.373 | Likely Benign | -0.80 | Neutral | 0.016 | Benign | 0.002 | Benign | 1.32 | Pathogenic | 0.55 | Tolerated | 0.0978 | 0.4313 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| 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.2157C>A | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, ESM1b, and Foldetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.250 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2157C>G | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect, whereas polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. FoldX, Rosetta, ESM1b, and Foldetta are inconclusive. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign outcome; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.244 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.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.2861C>T | P954L 2D  AIThe SynGAP1 missense variant P954L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.607 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.43 | Neutral | 0.977 | Probably Damaging | 0.812 | Possibly Damaging | 2.78 | Benign | 0.55 | Tolerated | 0.2346 | 0.5867 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.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.2881C>T | H961Y 2D AIThe SynGAP1 missense variant H961Y is listed in ClinVar with an uncertain significance (ClinVar ID 862637.0) and is present in gnomAD (ID 6‑33443433‑C‑T). 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 a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | Conflicting | 2 | 6-33443433-C-T | 3 | 1.86e-6 | -8.051 | Likely Pathogenic | 0.157 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.07 | Neutral | 0.716 | Possibly Damaging | 0.147 | Benign | 4.10 | Benign | 0.55 | Tolerated | 3.77 | 5 | 0.1369 | 0.4563 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||
| c.3011A>T | H1004L 2D AIThe SynGAP1 missense variant H1004L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign votes). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the balance of evidence leans toward a benign interpretation, 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. | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.179 | Likely Benign | 0.716 | Likely Pathogenic | Likely Benign | 0.220 | Likely Benign | -3.14 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.75 | Benign | 0.55 | Tolerated | 0.1223 | 0.6026 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3166G>A | G1056S 2D AIThe SynGAP1 missense variant G1056S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). 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. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -5.252 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.339 | Likely Benign | -0.28 | Neutral | 0.451 | Benign | 0.149 | Benign | 1.87 | Pathogenic | 0.55 | Tolerated | 0.2497 | 0.5702 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3173G>C | G1058A 2D AIThe SynGAP1 missense variant G1058A 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, derived from a 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 | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -6.823 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.21 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.29 | Benign | 0.55 | Tolerated | 0.3288 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3217T>A | S1073T 2D AIThe SynGAP1 missense variant S1073T 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -5.203 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -0.26 | Neutral | 0.025 | Benign | 0.026 | Benign | 4.06 | Benign | 0.55 | Tolerated | 0.1696 | 0.6509 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3394T>G | S1132A 2D AIThe SynGAP1 missense variant S1132A 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 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -3.401 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -0.60 | Neutral | 0.061 | Benign | 0.013 | Benign | 5.47 | Benign | 0.55 | Tolerated | 0.4416 | 0.5683 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3484C>T | P1162S 2D AIThe SynGAP1 missense variant P1162S is listed in ClinVar (ID 2287942.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of high‑accuracy and consensus predictions lean toward a benign impact. Thus, the variant is most likely benign, which is consistent with its ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | Uncertain | 1 | -2.118 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.215 | Likely Benign | -1.93 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.55 | Tolerated | 3.88 | 3 | 0.3386 | 0.6055 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3541A>G | K1181E 2D AIThe SynGAP1 missense variant K1181E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense (Default and Optimized) 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 show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward 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 | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | -3.244 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -1.19 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 2.86 | Benign | 0.55 | Tolerated | 0.2862 | 0.0877 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.673T>A | S225T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -6.351 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.64 | Ambiguous | 0.4 | 0.59 | Ambiguous | 0.62 | Ambiguous | 0.03 | Likely Benign | 0.244 | Likely Benign | -1.98 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.73 | Benign | 0.55 | Tolerated | 0.1419 | 0.7395 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1186G>A | G396S 2D AIThe SynGAP1 missense variant G396S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.934 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 1.76 | Ambiguous | 1.6 | 1.12 | Ambiguous | 1.44 | Ambiguous | 0.10 | Likely Benign | 0.223 | Likely Benign | -0.99 | Neutral | 0.004 | Benign | 0.003 | Benign | 3.93 | Benign | 0.56 | Tolerated | 0.2668 | 0.4894 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2315T>C | F772S 2D AIThe SynGAP1 missense variant F772S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are not available. Overall, the preponderance of evidence points to a benign effect for F772S, 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.722 | Likely Benign | 0.442 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -0.26 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.21 | Benign | 0.56 | Tolerated | 0.4134 | 0.0558 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2478C>A | D826E 2D AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2478C>G | D826E 2D AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2521G>C | V841L 2D AIThe SynGAP1 missense variant V841L is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -7.924 | In-Between | 0.514 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -0.01 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.85 | Benign | 0.56 | Tolerated | 0.0850 | 0.4233 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2521G>T | V841L 2D AIThe SynGAP1 missense variant V841L is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -7.924 | In-Between | 0.514 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -0.01 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.85 | Benign | 0.56 | Tolerated | 0.0850 | 0.4233 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2563C>G | L855V 2D AIThe SynGAP1 missense variant L855V 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. 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 | 0.724957 | Disordered | 0.485558 | Uncertain | 0.285 | 0.823 | 0.625 | -3.866 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.71 | Neutral | 0.059 | Benign | 0.037 | Benign | 4.10 | Benign | 0.56 | Tolerated | 0.1621 | 0.3731 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2767A>C | I923L 2D AIThe SynGAP1 missense variant I923L is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—including REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 | 0.562014 | Disordered | 0.964857 | Binding | 0.292 | 0.852 | 0.250 | -1.637 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.03 | Neutral | 0.166 | Benign | 0.101 | Benign | 2.82 | Benign | 0.56 | Tolerated | 0.1133 | 0.4528 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2871T>A | H957Q 2D AIThe SynGAP1 missense variant H957Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.304 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.87 | Neutral | 0.255 | Benign | 0.105 | Benign | 2.54 | Benign | 0.56 | Tolerated | 0.2227 | 0.4114 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2871T>G | H957Q 2D AIThe SynGAP1 missense variant H957Q 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.304 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.87 | Neutral | 0.255 | Benign | 0.105 | Benign | 2.54 | Benign | 0.56 | Tolerated | 0.2227 | 0.4114 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3016T>G | Y1006D 2D  AIThe SynGAP1 missense variant Y1006D is catalogued in gnomAD (variant ID 6‑33443568‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/ Rosetta) stability data are available. Considering the high‑accuracy consensus, the variant is most likely benign; 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 | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | 6-33443568-T-G | -5.296 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -1.53 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.56 | Tolerated | 3.77 | 5 | 0.3776 | 0.1094 | -3 | -4 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||
| c.3078C>A | D1026E 2D AIThe SynGAP1 missense variant D1026E is listed in ClinVar (ID 4746138) as benign and is not reported in gnomAD. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No tool predicts pathogenicity. Grouping by agreement, all predictors fall into the benign category, with no pathogenic calls. High‑accuracy assessments reinforce this view: 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence strongly supports a benign classification, fully consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | Benign | 1 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 0.1449 | 0.4783 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3078C>G | D1026E 2D AIThe SynGAP1 missense variant D1026E 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 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, 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 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 | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 0.1449 | 0.4783 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>C | V1078L 2D AIThe SynGAP1 missense variant V1078L 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, 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, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that V1078L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.547 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -0.16 | Neutral | 0.451 | Benign | 0.209 | Benign | 4.13 | Benign | 0.56 | Tolerated | 0.0889 | 0.5349 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3377G>C | G1126A 2D AIThe SynGAP1 missense variant G1126A 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, derived from a 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 | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -6.402 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.228 | Likely Benign | -0.63 | Neutral | 0.124 | Benign | 0.061 | Benign | 4.83 | Benign | 0.56 | Tolerated | 0.3505 | 0.5333 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3472G>C | V1158L 2D AIThe SynGAP1 missense variant V1158L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Benign; Foldetta results are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions, plus a benign consensus) points to a benign classification, and this does not contradict any ClinVar status because no ClinVar claim exists. Thus, the variant is most likely benign, though the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -2.345 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.187 | Likely Benign | -0.73 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.78 | Benign | 0.56 | Tolerated | 0.1066 | 0.4642 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1019C>T | A340V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A340V variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, 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 the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is uncertain and therefore unavailable for interpretation. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -6.427 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.69 | Ambiguous | 0.3 | 0.32 | Likely Benign | 0.51 | Ambiguous | 0.40 | Likely Benign | 0.102 | Likely Benign | -1.81 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 2.09 | Pathogenic | 0.57 | Tolerated | 0.1197 | 0.5780 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| 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.1441C>A | H481N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H481N 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—Rosetta and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.229 | Likely Pathogenic | 0.381 | Ambiguous | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.35 | Likely Benign | 0.09 | Likely Benign | 0.205 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.68 | Benign | 0.57 | Tolerated | 0.1205 | 0.1631 | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||
| 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.1744G>C | E582Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E582Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments—AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—all predict a benign impact, with Foldetta combining FoldX‑MD and Rosetta stability outputs. In contrast, the two polyPhen‑2 scores and AlphaMissense‑Default suggest pathogenicity, but these are outnumbered by benign predictions. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -3.700 | Likely Benign | 0.605 | Likely Pathogenic | Likely Benign | 0.17 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.19 | Likely Benign | -0.24 | Likely Benign | 0.138 | Likely Benign | -0.61 | Neutral | 0.992 | Probably Damaging | 0.993 | Probably Damaging | 3.22 | Benign | 0.57 | Tolerated | 0.0979 | 0.3402 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| 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.3292A>G | S1098G 2D AIThe SynGAP1 missense variant S1098G 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the collective predictions strongly support a benign impact, and this conclusion is consistent with the lack of a ClinVar pathogenic classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -3.494 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.39 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.72 | Benign | 0.57 | Tolerated | 0.2634 | 0.5206 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3367G>A | G1123S 2D AIThe SynGAP1 missense variant G1123S is reported in gnomAD (variant ID 6-33443919-G-A) but has no ClinVar entry. 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, 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 | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | 6-33443919-G-A | -4.918 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.291 | Likely Benign | -0.32 | Neutral | 0.292 | Benign | 0.157 | Benign | 4.66 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0.2554 | 0.5111 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3367G>C | G1123R 2D AIThe SynGAP1 missense variant G1123R is not reported in ClinVar (no entry) and is absent from gnomAD. Consensus from routine in silico predictors shows a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains 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 no Foldetta stability data are available. Consequently, the overall evidence points to a benign effect for G1123R. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -9.104 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 0.330 | Likely Benign | -0.46 | Neutral | 0.802 | Possibly Damaging | 0.435 | Benign | 4.34 | Benign | 0.57 | Tolerated | 0.0933 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3859C>G | P1287A 2D AIThe SynGAP1 missense variant P1287A 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 classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -3.064 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.91 | Benign | 0.57 | Tolerated | 0.2885 | 0.3222 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3964G>T | A1322S 2D AIThe SynGAP1 missense variant A1322S is catalogued in gnomAD (ID 6‑33451838‑G‑T) 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 variant 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 results are not available. Overall, the evidence strongly supports a benign classification, 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 | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-T | -4.570 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 1.38 | Neutral | 0.003 | Benign | 0.001 | Benign | 4.48 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0.2954 | 0.6084 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.596A>G | N199S 2D AIThe SynGAP1 missense variant N199S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the variant as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the variant is most likely benign, and this prediction does not contradict the 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 | -0.268 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.4 | -0.08 | Likely Benign | 0.00 | Likely Benign | -0.44 | Likely Benign | 0.040 | Likely Benign | 0.09 | Neutral | 0.160 | Benign | 0.045 | Benign | 4.36 | Benign | 0.57 | Tolerated | 0.2601 | 0.6023 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.670A>G | T224A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T224A is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435521‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | Conflicting | 4 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | 0.464 | Likely Benign | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 0.4253 | 0.5053 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.826C>G | P276A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P276A is reported in gnomAD (variant ID 6‑33437731‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods give a benign signal: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is available). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | 6-33437731-C-G | 5 | 3.10e-6 | -3.414 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.22 | Ambiguous | 0.50 | Likely Benign | 0.187 | Likely Benign | -2.31 | Neutral | 0.044 | Benign | 0.030 | Benign | 1.98 | Pathogenic | 0.57 | Tolerated | 3.38 | 19 | 0.3149 | 0.3669 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||
| 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.1129A>C | M377L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377L is catalogued in gnomAD (ID 6‑33438034‑A‑C) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. Only Rosetta yields an uncertain result, which is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | 6-33438034-A-C | 1 | 1.95e-6 | -2.394 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.69 | Ambiguous | 0.41 | Likely Benign | 0.16 | Likely Benign | 0.175 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.58 | Tolerated | 4.32 | 12 | 0.2516 | 0.4885 | 2 | 4 | 1.9 | -18.03 | ||||||||||||||||||||||||
| c.1129A>T | M377L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377L is reported in gnomAD (variant ID 6‑33438034‑A‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus all classify the change as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. No inconclusive or missing predictions are present. Based on the collective evidence, the variant is most likely benign, and this assessment is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | 6-33438034-A-T | -2.394 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.69 | Ambiguous | 0.41 | Likely Benign | 0.16 | Likely Benign | 0.186 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.58 | Tolerated | 4.32 | 12 | 0.2516 | 0.4885 | 2 | 4 | 1.9 | -18.03 | ||||||||||||||||||||||||||
| c.1286G>A | R429Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438191‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while premPS is inconclusive. The high‑accuracy consensus (SGM Consensus) – a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – yields a “Likely Benign” result. AlphaMissense‑Optimized itself predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Taken together, the preponderance of evidence points to a benign impact for R429Q, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | Uncertain | 2 | 6-33438191-G-A | 10 | 6.20e-6 | -8.227 | Likely Pathogenic | 0.143 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.41 | Likely Benign | 0.98 | Ambiguous | 0.156 | Likely Benign | -1.25 | Neutral | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.47 | Benign | 0.58 | Tolerated | 3.38 | 25 | 0.2518 | 0.1985 | 1 | 1 | 1.0 | -28.06 | 235.8 | 59.5 | 0.0 | 0.0 | -0.3 | 0.4 | X | Potentially Pathogenic | The guanidinium group of the Arg429 side chain, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or an H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, Gln429 cannot form ionic interactions with the acidic residues; however, the carboxamide group can form multiple H-bonds. The H-bonding coordination of the Asn429 side chain varied between the replica simulations. In one simulation, three H-bonds were formed simultaneously with the Asp467 side chain, the backbone carbonyl group of Asn426, and the amide group of Met430 at the end of the same α helix. The residue swap could affect the tertiary structure assembly during folding due to weaker bond formation, but no large-scale negative effects were seen during the simulations. | |||||||||||||
| c.1951G>C | E651Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E651Q is not 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 change as benign. No tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign result. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -6.308 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.14 | Likely Benign | -0.13 | Likely Benign | 0.158 | Likely Benign | -1.23 | Neutral | 0.244 | Benign | 0.075 | Benign | 3.34 | Benign | 0.58 | Tolerated | 0.1438 | 0.5893 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.3097T>A | S1033T 2D AIThe SynGAP1 missense variant S1033T is not reported 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, 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 indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.702 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.05 | Neutral | 0.568 | Possibly Damaging | 0.171 | Benign | 2.73 | Benign | 0.58 | Tolerated | 0.1379 | 0.6089 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>C | N1090T 2D AIThe SynGAP1 missense variant N1090T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (both HumDiv and HumVar tracks) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. Overall, the preponderance of evidence points to a benign effect for 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 | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.478 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -0.78 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.77 | Benign | 0.58 | Tolerated | 0.1451 | 0.7930 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3397A>G | I1133V 2D AIThe SynGAP1 missense variant I1133V is listed in ClinVar as Benign (ClinVar ID 999690.0) and is present in the gnomAD database (gnomAD ID 6‑33443949‑A‑G). 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 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, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | Benign | 1 | 6-33443949-A-G | 22 | 1.48e-5 | -3.362 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.180 | Likely Benign | 0.06 | Neutral | 0.007 | Benign | 0.007 | Benign | 5.47 | Benign | 0.58 | Tolerated | 4.32 | 3 | 0.1190 | 0.3985 | 4 | 3 | -0.3 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| 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.3489C>A | H1163Q 2D AIThe SynGAP1 missense variant H1163Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1163Q. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.970 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.43 | Benign | 0.58 | Tolerated | 0.1445 | 0.3424 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3489C>G | H1163Q 2D AIThe SynGAP1 missense variant H1163Q is not 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 FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar reporting and gnomAD presence, 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 | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.970 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.43 | Benign | 0.58 | Tolerated | 0.1445 | 0.3424 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>T | P1304S 2D AIThe SynGAP1 missense variant P1304S is reported in gnomAD (ID 6‑33451784‑C‑T) but has no ClinVar entry. 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 predict a benign effect. No tool in the dataset indicates 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 not available. Based on the collective 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451784-C-T | 1 | 6.20e-7 | -4.103 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.36 | Neutral | 0.059 | Benign | 0.041 | Benign | 3.03 | Benign | 0.58 | Tolerated | 3.77 | 5 | 0.2900 | 0.4442 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.673T>G | S225A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225A is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive (uncertain) and therefore does not alter the overall benign assessment. Consequently, the variant is most likely benign based on the available predictions, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -3.752 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.3 | 0.79 | Ambiguous | 0.55 | Ambiguous | 0.11 | Likely Benign | 0.201 | Likely Benign | -1.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.79 | Benign | 0.58 | Tolerated | 0.4840 | 0.5897 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.992C>T | S331L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only FATHMM predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the consensus of the majority of tools supports a benign classification, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar 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 | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -6.570 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.0 | 1.06 | Ambiguous | 0.80 | Ambiguous | 0.07 | Likely Benign | 0.090 | Likely Benign | -1.72 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.87 | Pathogenic | 0.58 | Tolerated | 0.0953 | 0.4124 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| 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.1270G>C | V424L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely benign classification. Stability‑based methods are inconclusive: FoldX is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -4.941 | Likely Benign | 0.742 | Likely Pathogenic | Likely Benign | -0.90 | Ambiguous | 0.2 | -0.41 | Likely Benign | -0.66 | Ambiguous | 0.43 | Likely Benign | 0.159 | Likely Benign | -1.68 | Neutral | 0.327 | Benign | 0.026 | Benign | 4.50 | Benign | 0.59 | Tolerated | 0.1018 | 0.2680 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1441C>T | H481Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481Y is listed in ClinVar as benign (ClinVar ID 1543764.0) and is present in the gnomAD database (gnomAD ID 6‑33438473‑C‑T). Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta report uncertain stability effects. 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 uncertain. Taking all available evidence together, the variant is most likely benign, which is consistent with its ClinVar benign annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | Likely Benign | 1 | 6-33438473-C-T | 16 | 9.91e-6 | -10.910 | Likely Pathogenic | 0.565 | Likely Pathogenic | Likely Benign | -0.53 | Ambiguous | 0.1 | -0.46 | Likely Benign | -0.50 | Ambiguous | 0.20 | Likely Benign | 0.256 | Likely Benign | -3.32 | Deleterious | 0.988 | Probably Damaging | 0.979 | Probably Damaging | 3.40 | Benign | 0.59 | Tolerated | 3.37 | 33 | 0.0610 | 0.3558 | 0 | 2 | 1.9 | 26.03 | 256.5 | -44.4 | 0.0 | 0.0 | 0.2 | 0.2 | X | X | Uncertain | The imidazole ring of the His481 side chain is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. In the WT simulations, His481 alternately stacks against Arg485, Arg587, and Glu480 without a definite role. In the variant simulations, Tyr481 also alternately stacks with nearby arginine residues, including Arg485, Arg587, and Arg479. The interaction between Tyr481 and Arg479 affects the α-α loop, causing it to fold into a distorted helical structure, an effect that might be more pronounced during protein folding. Finally, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||
| c.2257G>T | A753S 2D AIThe SynGAP1 missense variant A753S is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -3.656 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.25 | Neutral | 0.062 | Benign | 0.015 | Benign | 3.03 | Benign | 0.59 | Tolerated | 0.2905 | 0.5899 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.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.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.2977C>T | P993S 2D AIThe SynGAP1 missense variant P993S is reported in gnomAD (ID 6‑33443529‑C‑T) 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 pathogenicity, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | 6-33443529-C-T | 3 | 1.86e-6 | -3.665 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.13 | Neutral | 0.011 | Benign | 0.023 | Benign | 4.26 | Benign | 0.59 | Tolerated | 4.32 | 2 | 0.3421 | 0.5465 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| 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.3157A>G | S1053G 2D AIThe SynGAP1 missense variant S1053G 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 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, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that S1053G 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -1.016 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.57 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.32 | Benign | 0.59 | Tolerated | 0.2724 | 0.5046 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3304G>T | A1102S 2D AIThe SynGAP1 missense variant A1102S 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 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 | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | -2.900 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.05 | Neutral | 0.019 | Benign | 0.032 | Benign | 2.57 | Benign | 0.59 | Tolerated | 0.2666 | 0.6501 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3604A>C | I1202L 2D AIThe SynGAP1 I1202L missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.510422 | Binding | 0.874 | 0.593 | 0.250 | -8.026 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -1.27 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.94 | Pathogenic | 0.59 | Tolerated | 0.0788 | 0.2874 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.1040C>A | T347N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347N is listed in ClinVar with an uncertain significance (ClinVar ID 3672484.0) and is present in the gnomAD database (gnomAD ID 6‑33437945‑C‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the collective evidence points to a benign effect, aligning with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | Uncertain | 1 | 6-33437945-C-A | 9 | 5.58e-6 | -5.545 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.44 | Likely Benign | -0.06 | Likely Benign | 0.059 | Likely Benign | 1.96 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.67 | Pathogenic | 0.60 | Tolerated | 3.37 | 25 | 0.1070 | 0.4359 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||
| c.1189T>G | C397G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus all indicate a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies it as “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | 1.244 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.68 | Ambiguous | 0.2 | 1.42 | Ambiguous | 1.05 | Ambiguous | 0.04 | Likely Benign | 0.272 | Likely Benign | 1.51 | Neutral | 0.276 | Benign | 0.066 | Benign | 5.93 | Benign | 0.60 | Tolerated | 0.3678 | 0.3729 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1268A>T | Y423F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423F 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, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect, while premPS is inconclusive. High‑accuracy methods give consistent benign results: AlphaMissense‑Optimized is benign, the SGM‑Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the overwhelming majority of evidence supports 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 | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -5.533 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.03 | Likely Benign | 0.1 | -0.05 | Likely Benign | -0.01 | Likely Benign | 0.76 | Ambiguous | 0.149 | Likely Benign | -2.30 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.45 | Benign | 0.60 | Tolerated | 0.1934 | 0.2337 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.1406C>T | A469V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A469V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and Foldetta; premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts pathogenic. With seven tools supporting pathogenicity versus four supporting benignity, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -8.858 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 2.30 | Destabilizing | 0.4 | 2.66 | Destabilizing | 2.48 | Destabilizing | -0.77 | Ambiguous | 0.426 | Likely Benign | 0.26 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.20 | Pathogenic | 0.60 | Tolerated | 0.0827 | 0.5421 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.1426T>C | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, 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. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.196 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||||
| c.1428C>A | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, 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. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.180 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||||||
| c.1428C>G | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438460‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that returned uncertain results—FoldX, Rosetta, Foldetta, and premPS—do not contribute to the assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, with two pathogenic and two benign calls; Foldetta also reports an uncertain stability change. Overall, the balance of evidence favors a pathogenic effect for F476L, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | Uncertain | 2 | 6-33438460-C-G | 4 | 2.48e-6 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.180 | Likely Benign | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 0.1653 | 0.2916 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||||
| c.1609G>T | A537S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537S is reported in gnomAD (6-33438852-G-T) and has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. When predictions are grouped, the majority of tools (ten) support benign, whereas three tools support pathogenic. High‑accuracy assessments further reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Consequently, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 6-33438852-G-T | 1 | 6.20e-7 | -3.602 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | 0.46 | Likely Benign | 0.37 | Likely Benign | 0.28 | Likely Benign | 0.206 | Likely Benign | -0.66 | Neutral | 0.528 | Possibly Damaging | 0.592 | Possibly Damaging | -1.25 | Pathogenic | 0.60 | Tolerated | 3.37 | 35 | 0.2729 | 0.4431 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||
| c.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.2236G>A | V746M 2D  AIThe SynGAP1 missense variant V746M 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 in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of available predictions strongly suggests that V746M 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -4.194 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.010 | Likely Benign | -0.58 | Neutral | 0.065 | Benign | 0.037 | Benign | 2.79 | Benign | 0.60 | Tolerated | 0.0756 | 0.4576 | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2258C>A | A753D 2D AISynGAP1 missense variant A753D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign, while only polyPhen‑2 HumDiv predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy tools corroborate this view: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus likewise indicates Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, and this conclusion does not contradict the ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -5.836 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -1.66 | Neutral | 0.669 | Possibly Damaging | 0.265 | Benign | 2.60 | Benign | 0.60 | Tolerated | 0.2151 | 0.2200 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2398G>A | G800S 2D AIThe SynGAP1 missense variant G800S is reported as “Likely Benign” by the SGM‑Consensus method and is absent from ClinVar and gnomAD. All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -3.572 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.69 | Neutral | 0.292 | Benign | 0.157 | Benign | 2.78 | Benign | 0.60 | Tolerated | 0.2375 | 0.4923 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3170G>C | S1057T 2D AIThe SynGAP1 missense variant S1057T 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 (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 consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.375 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.241 | Likely Benign | -0.18 | Neutral | 0.625 | Possibly Damaging | 0.170 | Benign | 5.26 | Benign | 0.60 | Tolerated | 0.2289 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3238G>A | A1080T 2D AIThe SynGAP1 missense variant A1080T (ClinVar ID 1473274.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33443790‑G‑A). 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 in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “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 suggests the variant is most likely benign, which does not contradict the current ClinVar status of uncertainty. 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 | Conflicting | 2 | 6-33443790-G-A | 17 | 1.06e-5 | -3.928 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.19 | Neutral | 0.253 | Benign | 0.042 | Benign | 4.10 | Benign | 0.60 | Tolerated | 3.77 | 5 | 0.1564 | 0.7103 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3493T>G | S1165A 2D AIThe SynGAP1 missense variant S1165A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. When predictions are grouped by agreement, the benign‑predicating tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter this balance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta data are unavailable. Overall, the computational 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 | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.308 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -1.11 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.60 | Tolerated | 0.5363 | 0.4236 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3673T>A | S1225T 2D AIThe SynGAP1 missense variant S1225T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) reports likely benign; Foldetta results are not available. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -4.409 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.216 | Likely Benign | -0.49 | Neutral | 0.003 | Benign | 0.008 | Benign | 5.50 | Benign | 0.60 | Tolerated | 0.0972 | 0.4618 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3919C>A | P1307T 2D AIThe SynGAP1 missense variant P1307T 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 predicts 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) indicates a likely benign outcome. 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 suggests that P1307T is most likely benign, and this conclusion is consistent with the lack of ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.262 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.20 | Neutral | 0.386 | Benign | 0.266 | Benign | 3.07 | Benign | 0.60 | Tolerated | 0.1732 | 0.5436 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.502C>A | H168N 2D AIThe SynGAP1 missense variant H168N 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 all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tools predict pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -4.764 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.14 | Neutral | 0.016 | Benign | 0.015 | Benign | 4.29 | Benign | 0.60 | Tolerated | 0.1516 | 0.2589 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.944A>G | N315S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315S is not 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, 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. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. 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 the variant, 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 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -4.847 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.2 | 0.78 | Ambiguous | 0.82 | Ambiguous | 0.68 | Ambiguous | 0.250 | Likely Benign | -1.84 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.03 | Pathogenic | 0.60 | Tolerated | 0.4022 | 0.7395 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1267T>C | Y423H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y423H missense variant 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, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default. AlphaMissense‑Optimized is reported as uncertain. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and therefore inconclusive, while Foldetta predicts a pathogenic impact. Overall, the majority of evaluated tools (10 pathogenic vs. 4 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -6.638 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.77 | Destabilizing | 1.66 | Destabilizing | 0.257 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.61 | Tolerated | 0.1603 | 0.0352 | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||
| c.2071A>T | T691S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -9.274 | Likely Pathogenic | 0.123 | Likely Benign | Likely Benign | 0.44 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.34 | Likely Benign | 0.88 | Ambiguous | 0.041 | Likely Benign | -1.67 | Neutral | 0.860 | Possibly Damaging | 0.584 | Possibly Damaging | 3.49 | Benign | 0.61 | Tolerated | 0.2213 | 0.3343 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2291A>G | N764S 2D AIThe SynGAP1 missense variant N764S is listed in ClinVar as Benign (ClinVar ID 1948460.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, consistent with the ClinVar classification, and there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | Benign | 1 | -3.149 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.84 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.61 | Tolerated | 3.64 | 6 | 0.3762 | 0.5062 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||
| c.2471G>A | S824N 2D  AIThe SynGAP1 missense variant S824N is reported in gnomAD (6‑33443023‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | 6-33443023-G-A | 2 | 1.24e-6 | -4.473 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.08 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.61 | Tolerated | 3.77 | 5 | 0.1713 | 0.5327 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| c.2566A>G | N856D 2D AIThe SynGAP1 missense variant N856D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and consensus analyses indicates that the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.477615 | Uncertain | 0.263 | 0.827 | 0.500 | -4.636 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.25 | Neutral | 0.965 | Probably Damaging | 0.721 | Possibly Damaging | 4.17 | Benign | 0.61 | Tolerated | 0.1875 | 0.4895 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3151G>A | G1051S 2D AIThe SynGAP1 missense variant G1051S 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 substitution as benign. Only FATHMM predicts a pathogenic outcome. When the predictions are grouped, the benign consensus includes eight tools, whereas the pathogenic consensus contains a single tool. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta data are unavailable, so no stability inference can be drawn. Overall, the computational evidence overwhelmingly supports a benign classification for G1051S, and this conclusion is consistent with the absence of any ClinVar annotation. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -4.742 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.445 | Likely Benign | 0.10 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.61 | Tolerated | 0.2446 | 0.4911 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3547T>G | Y1183D 2D AISynGAP1 missense variant Y1183D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, a majority‑vote model of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts the variant as likely benign. High‑accuracy assessments further indicate AlphaMissense‑Optimized as pathogenic, whereas Foldetta (FoldX‑MD/Rosetta stability analysis) is not available for this residue. Overall, the balance of evidence leans toward a benign effect, and this assessment does not conflict with ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.718 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.10 | Neutral | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 2.83 | Benign | 0.61 | Tolerated | 0.4602 | 0.0243 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.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.1994A>C | Y665S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic, and Foldetta is uncertain (treated as unavailable). Overall, the balance of evidence, particularly the pathogenic signal from the SGM Consensus and the equal split among standard predictors, indicates that the variant is most likely 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. | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | -9.110 | Likely Pathogenic | 0.453 | Ambiguous | Likely Benign | 1.24 | Ambiguous | 0.2 | 1.40 | Ambiguous | 1.32 | Ambiguous | 0.87 | Ambiguous | 0.202 | Likely Benign | -2.50 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.55 | Benign | 0.62 | Tolerated | 0.3995 | 0.1793 | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||
| c.2311T>G | S771A 2D AIThe SynGAP1 missense variant S771A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -4.337 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.09 | Neutral | 0.025 | Benign | 0.014 | Benign | 4.09 | Benign | 0.62 | Tolerated | 0.5201 | 0.4745 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.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.2893C>G | H965D 2D AIThe SynGAP1 missense variant H965D is reported in gnomAD (6‑33443445‑C‑G) and has no ClinVar entry. Consensus from most in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the change as benign, while only the ESM1b model flags it as pathogenic. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized returns a benign score, 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, did not provide a result for this residue, so its status is unavailable. Overall, the preponderance of evidence indicates that H965D is most likely benign, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.978700 | Binding | 0.342 | 0.882 | 0.750 | 6-33443445-C-G | 1 | 6.20e-7 | -9.827 | Likely Pathogenic | 0.192 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -0.94 | Neutral | 0.007 | Benign | 0.018 | Benign | 4.09 | Benign | 0.62 | Tolerated | 3.77 | 5 | 0.2697 | 0.3066 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.2918G>C | G973A 2D AIThe SynGAP1 missense variant G973A is reported in gnomAD (ID 6‑33443470‑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 classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment 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 | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | 6-33443470-G-C | 1 | 6.20e-7 | -3.847 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.14 | Neutral | 0.112 | Benign | 0.028 | Benign | 4.30 | Benign | 0.62 | Tolerated | 4.32 | 2 | 0.3405 | 0.5133 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2972G>C | G991A 2D AIThe SynGAP1 missense variant G991A is catalogued in gnomAD (ID 6‑33443524‑G‑C) and has no ClinVar entry. All evaluated in silico predictors report a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized are unanimous in predicting benign. No tool indicates pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” while Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | 6-33443524-G-C | 1 | 6.20e-7 | -3.585 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.83 | Neutral | 0.002 | Benign | 0.026 | Benign | 4.20 | Benign | 0.62 | Tolerated | 4.32 | 2 | 0.3522 | 0.4528 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.3028T>C | F1010L 2D AIThe SynGAP1 missense variant F1010L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and AlphaMissense‑Optimized is currently uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -1.982 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.099 | Likely Benign | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 0.2538 | 0.3245 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3030T>A | F1010L 2D AIThe SynGAP1 missense variant F1010L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and AlphaMissense‑Optimized is currently uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -1.982 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 0.2538 | 0.3245 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3030T>G | F1010L 2D AIThe SynGAP1 missense variant F1010L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign classification, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for F1010L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -1.982 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 0.2538 | 0.3245 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3296A>C | Y1099S 2D AIThe SynGAP1 missense variant Y1099S 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 trend: 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -1.775 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.23 | Neutral | 0.149 | Benign | 0.026 | Benign | 2.90 | Benign | 0.62 | Tolerated | 0.4564 | 0.2298 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3365G>C | G1122A 2D AIThe SynGAP1 missense variant G1122A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no conflict with ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -6.692 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.168 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.52 | Benign | 0.62 | Tolerated | 0.3487 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3965C>G | A1322G 2D AIThe SynGAP1 missense variant A1322G is catalogued in gnomAD (ID 6‑33451839‑C‑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 indicates a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign status. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this prediction 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 | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-G | -4.159 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.42 | Neutral | 0.005 | Benign | 0.002 | Benign | 4.16 | Benign | 0.62 | Tolerated | 3.77 | 5 | 0.2160 | 0.4741 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.1270G>A | V424I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. The only inconclusive results come from FoldX (uncertain) and Foldetta (uncertain). When high‑accuracy methods are considered separately, AlphaMissense‑Optimized predicts benign, the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also predicts benign, while Foldetta remains uncertain. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -3.814 | Likely Benign | 0.095 | Likely Benign | Likely Benign | -1.04 | Ambiguous | 0.1 | -0.48 | Likely Benign | -0.76 | Ambiguous | 0.02 | Likely Benign | 0.084 | Likely Benign | -0.15 | Neutral | 0.013 | Benign | 0.006 | Benign | 3.50 | Benign | 0.63 | Tolerated | 0.0874 | 0.2609 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.1379A>G | K460R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K460R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Taken together, the overwhelming majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -5.349 | Likely Benign | 0.175 | Likely Benign | Likely Benign | -0.41 | Likely Benign | 0.0 | 0.63 | Ambiguous | 0.11 | Likely Benign | 0.55 | Ambiguous | 0.103 | Likely Benign | -1.52 | Neutral | 0.991 | Probably Damaging | 0.962 | Probably Damaging | 3.46 | Benign | 0.63 | Tolerated | 0.5093 | 0.1169 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||
| c.3139T>A | S1047T 2D AIThe SynGAP1 missense variant S1047T 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 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, 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 | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | -4.222 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.029 | Likely Benign | 0.23 | Neutral | 0.069 | Benign | 0.049 | Benign | 2.63 | Benign | 0.63 | Tolerated | 0.1796 | 0.6265 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3160G>A | G1054S 2D AIThe SynGAP1 missense variant G1054S is listed in ClinVar (ID 699126.0) as Benign and is present in gnomAD (variant ID 6‑33443712‑G‑A). 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 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) yields Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Benign | 1 | 6-33443712-G-A | 32 | 1.99e-5 | -5.294 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.21 | Neutral | 0.121 | Benign | 0.013 | Benign | 4.04 | Benign | 0.63 | Tolerated | 3.77 | 5 | 0.2506 | 0.5311 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3479A>C | N1160T 2D AIThe SynGAP1 missense variant N1160T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.017 | Likely Benign | 0.889 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -3.61 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.81 | Pathogenic | 0.63 | Tolerated | 0.1147 | 0.6759 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.751A>C | K251Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar, while premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence supports a benign classification for K251Q, and this conclusion does not contradict the absence of a ClinVar entry. Based on the aggregate predictions, K251Q is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -5.869 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.36 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.39 | Likely Benign | -0.62 | Ambiguous | 0.465 | Likely Benign | 0.55 | Neutral | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.86 | Benign | 0.63 | Tolerated | 0.4466 | 0.1085 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.971G>T | R324L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324L is catalogued in gnomAD (6-33437876‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and SIFT; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta outputs) reports a benign stability change. Overall, the majority of evidence points toward 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 Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | 6-33437876-G-T | 1 | 6.20e-7 | -10.328 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.28 | Likely Benign | 0.0 | -0.08 | Likely Benign | -0.18 | Likely Benign | 0.29 | Likely Benign | 0.489 | Likely Benign | -2.20 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.86 | Pathogenic | 0.63 | Tolerated | 3.39 | 22 | 0.2310 | 0.5607 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||
| 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.1109G>A | G370D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, Foldetta (a folding‑stability method that integrates FoldX‑MD and Rosetta outputs) predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -5.332 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 3.64 | Destabilizing | 3.8 | 0.83 | Ambiguous | 2.24 | Destabilizing | 0.30 | Likely Benign | 0.372 | Likely Benign | -0.44 | Neutral | 0.007 | Benign | 0.001 | Benign | 1.32 | Pathogenic | 0.64 | Tolerated | 0.1632 | 0.1494 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||
| c.1198G>C | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is listed in ClinVar as Benign (ClinVar ID 1166313) and is present in gnomAD (6‑33438103‑G‑C). Prediction tools that agree on a benign effect include REVEL, FoldX‑MD (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Benign/Likely benign | 2 | 6-33438103-G-C | 22 | 1.36e-5 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | 0.325 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 0.1006 | 0.5242 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.1198G>T | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective evidence, 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 | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | 0.325 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 0.1006 | 0.5242 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||
| c.1675T>A | C559S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C559S is not 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, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools, premPS and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. Based on the overall distribution of predictions, the variant is most likely pathogenic; this conclusion does not contradict the ClinVar status, which has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -10.756 | Likely Pathogenic | 0.785 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.0 | -0.31 | Likely Benign | -0.17 | Likely Benign | 0.65 | Ambiguous | 0.450 | Likely Benign | -7.26 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.64 | Tolerated | 0.3940 | 0.1319 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1676G>C | C559S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C559S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: premPS (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -10.756 | Likely Pathogenic | 0.785 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.0 | -0.31 | Likely Benign | -0.17 | Likely Benign | 0.65 | Ambiguous | 0.469 | Likely Benign | -7.26 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.64 | Tolerated | 0.3940 | 0.1319 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1975T>G | S659A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while ESM1b remains uncertain. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -7.066 | In-Between | 0.117 | Likely Benign | Likely Benign | -0.31 | Likely Benign | 0.0 | 0.02 | Likely Benign | -0.15 | Likely Benign | 0.14 | Likely Benign | 0.088 | Likely Benign | -2.22 | Neutral | 0.097 | Benign | 0.114 | Benign | 3.50 | Benign | 0.64 | Tolerated | 0.4842 | 0.3813 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.2401G>C | G801R 2D AIThe SynGAP1 missense variant G801R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a benign outcome; Foldetta data are not available. Overall, the majority of evidence points to a benign effect, 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -4.226 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.18 | Neutral | 0.846 | Possibly Damaging | 0.624 | Possibly Damaging | 2.73 | Benign | 0.64 | Tolerated | 0.0850 | 0.3793 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2890C>A | H964N 2D AIThe SynGAP1 missense variant H964N 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), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. 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 | 0.990547 | Disordered | 0.982486 | Binding | 0.364 | 0.886 | 0.750 | -8.073 | Likely Pathogenic | 0.084 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.18 | Benign | 0.64 | Tolerated | 0.1988 | 0.3495 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3032G>C | G1011A 2D AIThe SynGAP1 missense variant G1011A is catalogued in gnomAD (ID 6‑33443584‑G‑C) and has no ClinVar entry. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments concur: 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 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 | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443584-G-C | -4.349 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.04 | Neutral | 0.139 | Benign | 0.089 | Benign | 2.89 | Benign | 0.64 | Tolerated | 3.77 | 5 | 0.3641 | 0.4571 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3143G>C | G1048A 2D AISynGAP1 missense variant G1048A 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 AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that G1048A 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 | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.821 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 0.3301 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>C | G1113R 2D AIThe SynGAP1 missense variant G1113R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.765 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.063 | Likely Benign | -1.54 | Neutral | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.65 | Benign | 0.64 | Tolerated | 0.0939 | 0.4426 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.82T>A | S28T 2D AIThe SynGAP1 missense variant S28T 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 any ClinVar pathogenic annotation. 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 | -3.810 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.21 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.64 | Tolerated | 0.1874 | 0.6140 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1721T>A | L574Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L574Q resides in the GAP domain. ClinVar contains no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; Rosetta’s assessment is uncertain. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | -3.015 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.2 | 0.52 | Ambiguous | 0.39 | Likely Benign | -0.18 | Likely Benign | 0.327 | Likely Benign | 2.53 | Neutral | 0.998 | Probably Damaging | 0.937 | Probably Damaging | -1.17 | Pathogenic | 0.65 | Tolerated | 0.1107 | 0.0888 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1964T>A | L655Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655Q is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for L655Q, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | Uncertain | 1 | -5.278 | Likely Benign | 0.144 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.69 | Ambiguous | 0.34 | Likely Benign | -0.15 | Likely Benign | 0.139 | Likely Benign | 0.61 | Neutral | 0.955 | Possibly Damaging | 0.602 | Possibly Damaging | 3.59 | Benign | 0.65 | Tolerated | 3.39 | 24 | 0.1248 | 0.0972 | -2 | -2 | -7.3 | 14.97 | 229.9 | -8.6 | 0.0 | 0.0 | 0.4 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu655, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Gln655 dynamically interacts with neighboring residues (e.g., Glu651, Glu656, Arg544) on the protein surface, with no negative structural effects. | ||||||||||||||||
| c.2117A>C | E706A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E706A has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen2_HumDiv suggests pathogenicity, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of ClinVar classification or gnomAD observation. Thus, the variant is most likely benign, and this is consistent with the lack of ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.377033 | Uncertain | 0.929 | 0.363 | 0.000 | -4.604 | Likely Benign | 0.443 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.48 | Likely Benign | 0.64 | Ambiguous | -0.12 | Likely Benign | 0.117 | Likely Benign | -0.81 | Neutral | 0.613 | Possibly Damaging | 0.180 | Benign | 4.20 | Benign | 0.65 | Tolerated | 0.3413 | 0.4089 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2258C>G | A753G 2D AIThe SynGAP1 missense variant A753G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -4.257 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.10 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 2.62 | Benign | 0.65 | Tolerated | 0.2447 | 0.5089 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2371A>G | K791E 2D AIThe SynGAP1 missense variant K791E is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while AlphaMissense‑Default remains uncertain. 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) indicates likely benign; Foldetta results are unavailable. Taken together, the preponderance of evidence supports a benign impact for K791E, 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 | 0.966441 | Disordered | 0.478670 | Uncertain | 0.356 | 0.896 | 0.875 | -3.823 | Likely Benign | 0.465 | Ambiguous | Likely Benign | 0.053 | Likely Benign | -0.58 | Neutral | 0.451 | Benign | 0.193 | Benign | 4.22 | Benign | 0.65 | Tolerated | 0.4829 | 0.0876 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3048C>A | D1016E 2D AIThe SynGAP1 missense variant D1016E is reported in ClinVar (ID 3803472.0) as benign and is present in gnomAD (variant ID 6‑33443600‑C‑A). 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. 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, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar benign classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | Likely Benign | 1 | 6-33443600-C-A | 2 | 1.24e-6 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 0.2237 | 0.6898 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3048C>G | D1016E 2D AIThe SynGAP1 missense variant D1016E 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, so they do not influence the overall assessment. **Thus, 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 | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 0.2237 | 0.6898 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3081C>A | N1027K 2D AIThe SynGAP1 missense variant N1027K is not reported 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, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3081C>G | N1027K 2D AIThe SynGAP1 missense variant N1027K is not reported 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, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.370G>T | A124S 2D AIThe SynGAP1 missense variant A124 S 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 reinforce this view: 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -1.933 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.35 | Neutral | 0.849 | Possibly Damaging | 0.303 | Benign | 4.22 | Benign | 0.65 | Tolerated | 0.3018 | 0.6192 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3730A>G | S1244G 2D AIThe SynGAP1 missense variant S1244G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, 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 evidence therefore comes only from AlphaMissense‑Optimized, which predicts benign, while the other high‑accuracy tools are unavailable. Overall, the balance of evidence (five benign vs four pathogenic predictions, with the most reliable tool indicating benign) suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -8.304 | Likely Pathogenic | 0.221 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.77 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.12 | Pathogenic | 0.65 | Tolerated | 0.2267 | 0.3678 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3781A>G | S1261G 2D AIThe SynGAP1 missense variant S1261G 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), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from FATHMM. 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 results are not available. Overall, the majority of evidence supports a benign impact for S1261G, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -5.042 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.46 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.32 | Pathogenic | 0.65 | Tolerated | 0.2063 | 0.3477 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| 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.1288A>C | M430L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Rosetta, PolyPhen‑2 (HumDiv and HumVar), SIFT, and REVEL; no tool predicts pathogenicity. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all available evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -5.873 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.33 | Likely Benign | 0.1 | -0.10 | Likely Benign | 0.12 | Likely Benign | 0.72 | Ambiguous | 0.107 | Likely Benign | -1.07 | Neutral | 0.028 | Benign | 0.004 | Benign | 3.69 | Benign | 0.66 | Tolerated | 0.1767 | 0.5067 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1288A>T | M430L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Rosetta, PolyPhen‑2 (HumDiv and HumVar), SIFT, and REVEL; no tool predicts pathogenicity. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all available evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -5.873 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.33 | Likely Benign | 0.1 | -0.10 | Likely Benign | 0.12 | Likely Benign | 0.72 | Ambiguous | 0.107 | Likely Benign | -1.07 | Neutral | 0.028 | Benign | 0.004 | Benign | 3.69 | Benign | 0.66 | Tolerated | 0.1767 | 0.5067 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1382C>T | A461V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, 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) as pathogenic. Because the majority of standard predictors (nine benign vs. three pathogenic) favor a benign outcome, 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. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -9.968 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.3 | 0.34 | Likely Benign | 0.13 | Likely Benign | 0.02 | Likely Benign | 0.141 | Likely Benign | -3.05 | Deleterious | 0.983 | Probably Damaging | 0.273 | Benign | 3.43 | Benign | 0.66 | Tolerated | 0.0819 | 0.5078 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.1858T>G | S620A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from these analyses suggests a deleterious effect. Consequently, the variant is most likely benign based on the aggregate predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -4.637 | Likely Benign | 0.088 | Likely Benign | Likely Benign | -0.42 | Likely Benign | 0.0 | -0.90 | Ambiguous | -0.66 | Ambiguous | -0.19 | Likely Benign | 0.375 | Likely Benign | -0.52 | Neutral | 0.968 | Probably Damaging | 0.994 | Probably Damaging | -1.27 | Pathogenic | 0.66 | Tolerated | 0.4950 | 0.3636 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.2380C>A | P794T 2D AIThe SynGAP1 missense variant P794T is catalogued in gnomAD (ID 6‑33442932‑C‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), 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 dataset 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) also yields a benign prediction. The Foldetta stability analysis is not available for this variant. 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 | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | 6-33442932-C-A | 1 | 6.20e-7 | -4.838 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.34 | Neutral | 0.245 | Benign | 0.138 | Benign | 4.25 | Benign | 0.66 | Tolerated | 4.07 | 3 | 0.1739 | 0.6207 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||
| c.2924C>T | T975I 2D AIThe SynGAP1 missense variant T975I is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33443476‑C‑T). Prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” classification. 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. Overall, the computational evidence overwhelmingly supports a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | 6-33443476-C-T | 6 | 3.72e-6 | -3.912 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.66 | Neutral | 0.411 | Benign | 0.239 | Benign | 4.11 | Benign | 0.66 | Tolerated | 4.32 | 2 | 0.1107 | 0.5198 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||
| c.3554A>G | K1185R 2D AIThe SynGAP1 missense variant K1185R 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, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for K1185R, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -2.898 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -0.48 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.67 | Benign | 0.66 | Tolerated | 0.4476 | 0.0909 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.670A>T | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give 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) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.412 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.671C>G | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give 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) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.374 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.892C>G | P298A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, 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, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the preponderance of benign predictions and the lack of pathogenic consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -6.082 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.1 | 1.17 | Ambiguous | 1.20 | Ambiguous | 0.50 | Likely Benign | 0.191 | Likely Benign | -0.98 | Neutral | 0.885 | Possibly Damaging | 0.589 | Possibly Damaging | 1.94 | Pathogenic | 0.66 | Tolerated | 0.3761 | 0.5787 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.2350G>T | A784S 2D AIThe SynGAP1 missense variant A784S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | -2.233 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.41 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.72 | Benign | 0.67 | Tolerated | 0.2624 | 0.5171 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.914C>A | T305N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T305N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign, and the SGM‑Consensus score is “Likely Benign.” Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, and the combined Foldetta) return uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for T305N, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -3.261 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 1.18 | Ambiguous | 0.2 | 1.65 | Ambiguous | 1.42 | Ambiguous | 0.09 | Likely Benign | 0.098 | Likely Benign | 0.71 | Neutral | 0.046 | Benign | 0.040 | Benign | 2.34 | Pathogenic | 0.67 | Tolerated | 0.1327 | 0.4352 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.964G>T | A322S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this 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 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -1.424 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.2 | 0.38 | Likely Benign | 0.40 | Likely Benign | -0.44 | Likely Benign | 0.127 | Likely Benign | 1.09 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 0.67 | Tolerated | 0.2696 | 0.5253 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.990C>A | D330E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by 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. | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -3.427 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.2 | 2.31 | Destabilizing | 1.65 | Ambiguous | 0.39 | Likely Benign | 0.073 | Likely Benign | -1.38 | Neutral | 0.122 | Benign | 0.030 | Benign | 0.97 | Pathogenic | 0.67 | Tolerated | 0.1464 | 0.4416 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.990C>G | D330E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by 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. | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -3.427 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.2 | 2.31 | Destabilizing | 1.65 | Ambiguous | 0.39 | Likely Benign | 0.075 | Likely Benign | -1.38 | Neutral | 0.122 | Benign | 0.030 | Benign | 0.97 | Pathogenic | 0.67 | Tolerated | 0.1464 | 0.4416 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.991T>G | S331A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority vote (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is 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 | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -2.199 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.07 | Likely Benign | -0.15 | Likely Benign | 0.071 | Likely Benign | -0.44 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.89 | Pathogenic | 0.67 | Tolerated | 0.5314 | 0.3008 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.2497A>C | K833Q 2D AIThe SynGAP1 missense variant K833Q 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. 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, reports 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 stability analysis is unavailable. Overall, the consensus of most 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 | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -1.586 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.34 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.62 | Benign | 0.68 | Tolerated | 0.3744 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2800A>C | M934L 2D AIThe SynGAP1 missense variant M934L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. 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 not available. Overall, the consensus of all available predictions points to a benign impact, and this is consistent with the lack of a 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 | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -2.482 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.73 | Neutral | 0.002 | Benign | 0.002 | Benign | 3.03 | Benign | 0.68 | Tolerated | 0.2004 | 0.4051 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2800A>T | M934L 2D AIThe SynGAP1 missense variant M934L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. 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 not available. Consequently, the variant is most likely benign based on the collective predictions, 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 | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -2.482 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.73 | Neutral | 0.002 | Benign | 0.002 | Benign | 3.03 | Benign | 0.68 | Tolerated | 0.2004 | 0.4051 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2903G>C | G968A 2D AIThe SynGAP1 missense variant G968A is predicted to be benign by all available in‑silico tools. Consensus predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. No tools predict pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of ClinVar evidence, the variant is most likely benign and does not contradict any ClinVar status. 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 | -4.721 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.33 | Neutral | 0.245 | Benign | 0.140 | Benign | 4.24 | Benign | 0.68 | Tolerated | 0.3401 | 0.5154 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3343A>G | I1115V 2D AIThe SynGAP1 missense variant I1115V 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | -2.512 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.06 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.76 | Benign | 0.68 | Tolerated | 0.1561 | 0.3871 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3638A>G | N1213S 2D AIThe SynGAP1 missense variant N1213S is listed in ClinVar as Benign (ClinVar ID 708250.0) and is present in the gnomAD database (gnomAD ID 6‑33446630‑A‑G). 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 also as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Benign | 1 | 6-33446630-A-G | 13 | 8.05e-6 | -4.086 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.56 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.82 | Benign | 0.68 | Tolerated | 3.77 | 5 | 0.2607 | 0.4591 | 1 | 1 | 2.7 | -27.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||
| c.1195G>A | A399T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399T is listed in ClinVar (ID 1990638.0) as Benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the variant is most likely benign, and this conclusion aligns with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | Benign | 1 | -5.236 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 0.1 | 0.91 | Ambiguous | 1.08 | Ambiguous | 0.49 | Likely Benign | 0.272 | Likely Benign | -0.40 | Neutral | 0.131 | Benign | 0.039 | Benign | 5.41 | Benign | 0.69 | Tolerated | 3.38 | 26 | 0.1335 | 0.6477 | 1 | 0 | -2.5 | 30.03 | 211.4 | -41.4 | 0.0 | 0.0 | 0.6 | 0.4 | X | Potentially Pathogenic | The methyl group of Ala399, located in an anti-parallel β sheet strand (res. Ala399-Ile411), is swapped for a hydroxyl-containing threonine. In the variant simulations, the hydroxyl group of Thr399 can form H-bonds with the backbone atoms of the residues in the membrane-facing loops (e.g., Gly382) in the C2 domain. Consequently, the ability of the Thr399 side chain to form H-bonds with the membrane-facing loops could adversely affect the dynamics and stability of the SynGAP-membrane association. However, since the effects on the dynamics of the membrane-facing loops can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||
| c.1654T>A | C552S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552S is 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, and SIFT, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy assessments are mixed: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also indicates a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a benign effect. premPS is inconclusive. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for C552S. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -9.309 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | -0.27 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.31 | Likely Benign | 0.97 | Ambiguous | 0.748 | Likely Pathogenic | -8.21 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.15 | Pathogenic | 0.69 | Tolerated | 0.3469 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1655G>C | C552S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552S is 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, and SIFT, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy assessments are mixed: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also indicates a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a benign effect. premPS is inconclusive. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for C552S. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -9.309 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | -0.27 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.31 | Likely Benign | 0.97 | Ambiguous | 0.684 | Likely Pathogenic | -8.21 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.15 | Pathogenic | 0.69 | Tolerated | 0.3469 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.2294G>T | S765I 2D  AIThe SynGAP1 missense variant S765I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to 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 not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -6.891 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.187 | Likely Benign | -1.24 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.09 | Benign | 0.69 | Tolerated | 0.0768 | 0.5577 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2897A>G | H966R 2D AIThe SynGAP1 missense variant H966R is reported in gnomAD (ID 6‑33443449‑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 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 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 the majority of prediction tools and the high‑accuracy methods indicates that H966R 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 | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | 6-33443449-A-G | -5.474 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.71 | Neutral | 0.494 | Possibly Damaging | 0.170 | Benign | 4.06 | Benign | 0.69 | Tolerated | 4.32 | 2 | 0.2198 | 0.3410 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||
| c.1434A>C | E478D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -1.004 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | -0.65 | Ambiguous | -0.35 | Likely Benign | -0.28 | Likely Benign | 0.175 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.53 | Benign | 0.70 | Tolerated | 0.1768 | 0.3315 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1434A>T | E478D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -1.004 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | -0.65 | Ambiguous | -0.35 | Likely Benign | -0.28 | Likely Benign | 0.175 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.53 | Benign | 0.70 | Tolerated | 0.1768 | 0.3315 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| 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.2671C>G | L891V 2D AIThe SynGAP1 missense variant L891V 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 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 | 0.712013 | Disordered | 0.505861 | Binding | 0.305 | 0.923 | 0.750 | -4.992 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.65 | Neutral | 0.057 | Benign | 0.032 | Benign | 2.72 | Benign | 0.70 | Tolerated | 0.1614 | 0.2945 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2753C>G | A918G 2D AIThe SynGAP1 missense variant A918G is not reported 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 outcome. 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 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 computational evidence points to a benign effect, 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 | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -2.906 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.14 | Neutral | 0.954 | Possibly Damaging | 0.630 | Possibly Damaging | 2.72 | Benign | 0.70 | Tolerated | 0.2125 | 0.4376 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2998A>C | I1000L 2D AIThe SynGAP1 missense variant I1000L 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -2.103 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.34 | Neutral | 0.211 | Benign | 0.108 | Benign | 2.76 | Benign | 0.70 | Tolerated | 0.0916 | 0.4034 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3136C>T | P1046S 2D AIThe SynGAP1 missense variant P1046S is not 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), 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 computational evidence indicates a benign effect, and this consensus does not contradict any ClinVar status (none is available). 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 | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -3.909 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.72 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.39 | Pathogenic | 0.70 | Tolerated | 0.2929 | 0.5744 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3158G>C | S1053T 2D AIThe SynGAP1 missense variant S1053T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for S1053T, 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.209 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.25 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 5.32 | Benign | 0.70 | Tolerated | 0.2055 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3289C>T | P1097S 2D AIThe SynGAP1 missense variant P1097S 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 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 | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -3.748 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.04 | Neutral | 0.025 | Benign | 0.023 | Benign | 2.62 | Benign | 0.70 | Tolerated | 0.3332 | 0.5691 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3430T>G | L1144V 2D AIThe SynGAP1 missense variant L1144V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.025 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.227 | Likely Benign | -0.04 | Neutral | 0.952 | Possibly Damaging | 0.770 | Possibly Damaging | 5.43 | Benign | 0.70 | Tolerated | 0.1553 | 0.3297 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3583G>C | V1195L 2D AIThe SynGAP1 missense variant V1195L has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Considering the high‑accuracy tools, the consensus leans toward benign (SGM‑Consensus) with no definitive pathogenic signal from AlphaMissense‑Optimized or Foldetta. Overall, the majority of evidence supports a benign impact, and this assessment does not contradict any ClinVar status, as none exists for V1195L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -2.603 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.323 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.46 | Benign | 0.70 | Tolerated | 0.0695 | 0.3827 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3583G>T | V1195L 2D AIThe SynGAP1 missense variant V1195L has no ClinVar record and is not listed in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors (six benign vs. three pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, 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 | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -2.603 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.46 | Benign | 0.70 | Tolerated | 0.0695 | 0.3827 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2698A>T | T900S 2D AIThe SynGAP1 missense variant T900S 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 | 0.675549 | Disordered | 0.465347 | Uncertain | 0.289 | 0.924 | 0.375 | -2.031 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.17 | Neutral | 0.224 | Benign | 0.171 | Benign | 2.70 | Benign | 0.71 | Tolerated | 0.3311 | 0.4301 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3012C>A | H1004Q 2D AIThe SynGAP1 missense variant H1004Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.872 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.1831 | 0.3832 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.3012C>G | H1004Q 2D AIThe SynGAP1 missense variant H1004Q is catalogued in gnomAD (ID 6‑33443564‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while PolyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default 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 show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the preponderance of evidence (six benign predictions versus three pathogenic) indicates that H1004Q is most likely benign. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | 6-33443564-C-G | 3 | 1.86e-6 | -3.872 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.1831 | 0.3832 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.3332A>G | K1111R 2D AIThe SynGAP1 missense variant K1111R 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 | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -2.495 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.30 | Neutral | 0.006 | Benign | 0.006 | Benign | 2.74 | Benign | 0.71 | Tolerated | 0.4664 | 0.2031 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3853C>G | P1285A 2D AIThe SynGAP1 missense variant P1285A 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 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 | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | -3.902 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.52 | Neutral | 0.264 | Benign | 0.070 | Benign | 4.27 | Benign | 0.71 | Tolerated | 0.2944 | 0.2974 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3961C>T | P1321S 2D AIThe SynGAP1 missense variant P1321S is listed in ClinVar (ID 1806027.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33451835‑C‑T). 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 reports a pathogenic prediction. High‑accuracy assessments corroborate this benign trend: 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, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3610 | 0.5190 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3979C>T | P1327S 2D AIThe SynGAP1 missense variant P1327S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3098 | 0.4025 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.802A>G | I268V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign, while Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar 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 | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -4.553 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 1.46 | Ambiguous | 0.0 | 0.95 | Ambiguous | 1.21 | Ambiguous | 0.71 | Ambiguous | 0.139 | Likely Benign | -0.56 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.15 | Pathogenic | 0.71 | Tolerated | 0.0845 | 0.2489 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1021G>A | G341S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G341S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact for G341S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -3.206 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.3 | -1.46 | Ambiguous | -0.53 | Ambiguous | -0.67 | Ambiguous | 0.343 | Likely Benign | 0.73 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 0.37 | Pathogenic | 0.72 | Tolerated | 0.2416 | 0.4215 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2203A>C | S735R 2D AIThe SynGAP1 missense variant S735R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains 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 is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.318 | Likely Benign | 0.784 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 2.66 | Benign | 0.72 | Tolerated | 0.0913 | 0.2861 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2205C>A | S735R 2D AIThe SynGAP1 missense variant S735R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.318 | Likely Benign | 0.784 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 2.66 | Benign | 0.72 | Tolerated | 0.0913 | 0.2861 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2205C>G | S735R 2D AIThe SynGAP1 missense variant S735R has no ClinVar record and is not listed in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) remains Benign; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus three pathogenic predictions, a benign SGM‑Consensus, 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. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.318 | Likely Benign | 0.784 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 2.66 | Benign | 0.72 | Tolerated | 0.0913 | 0.2861 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2303A>G | D768G 2D  AIThe SynGAP1 D768G missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all predict benign, whereas AlphaMissense‑Default predicts pathogenic. The high‑accuracy AlphaMissense‑Optimized result is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, which would provide a protein‑folding stability assessment, has no available output for this variant. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -7.150 | In-Between | 0.697 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.03 | Neutral | 0.393 | Benign | 0.131 | Benign | 4.09 | Benign | 0.72 | Tolerated | 0.4130 | 0.7476 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.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.2897A>C | H966P 2D  AIThe SynGAP1 missense variant H966P 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 | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | -5.831 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.279 | Likely Benign | -0.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.72 | Tolerated | 0.2168 | 0.4301 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3049T>C | F1017L 2D AIThe SynGAP1 missense variant F1017L is listed in ClinVar (ID 3719654.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote) is benign. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | Benign | 1 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.3051C>A | F1017L 2D AIThe SynGAP1 missense variant F1017L is catalogued in gnomAD (ID 6‑33443603‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability data are available. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | 6-33443603-C-A | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.3051C>G | F1017L 2D AIThe SynGAP1 missense variant F1017L is not reported 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, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default 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 show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely 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 exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| 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.3940C>T | P1314S 2D AIThe SynGAP1 missense variant P1314S has no ClinVar entry and is not reported in gnomAD. 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 reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | -3.838 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.11 | Neutral | 0.005 | Benign | 0.003 | Benign | 4.22 | Benign | 0.72 | Tolerated | 0.3522 | 0.4751 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2935T>C | F979L 2D AIThe SynGAP1 missense variant F979L (ClinVar ID 1000410.0, status Uncertain, not found in gnomAD) has been evaluated by multiple in silico predictors. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, while pathogenic predictions are reported by polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports 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 effect, and this conclusion does not contradict the ClinVar status of Uncertain. 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 | Uncertain | 1 | -2.341 | Likely Benign | 0.870 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -1.00 | Neutral | 0.625 | Possibly Damaging | 0.430 | Benign | 4.22 | Benign | 0.73 | Tolerated | 4.32 | 2 | 0.2447 | 0.3876 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.2937C>A | F979L 2D AIThe SynGAP1 missense variant F979L has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default 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 show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.977500 | Binding | 0.274 | 0.889 | 0.625 | -2.341 | Likely Benign | 0.870 | Likely Pathogenic | Ambiguous | 0.328 | Likely Benign | -1.00 | Neutral | 0.625 | Possibly Damaging | 0.430 | Benign | 4.22 | Benign | 0.73 | Tolerated | 4.32 | 2 | 0.2447 | 0.3876 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.2937C>G | F979L 2D AIThe SynGAP1 missense variant F979L has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default 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 show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.977500 | Binding | 0.274 | 0.889 | 0.625 | -2.341 | Likely Benign | 0.870 | Likely Pathogenic | Ambiguous | 0.328 | Likely Benign | -1.00 | Neutral | 0.625 | Possibly Damaging | 0.430 | Benign | 4.22 | Benign | 0.73 | Tolerated | 4.32 | 2 | 0.2447 | 0.3876 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.964G>A | A322T 2D AIThe SynGAP1 missense variant A322T is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors classifies the change as benign: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. Only FATHMM indicates a pathogenic signal, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact on protein stability. Overall, the majority of evidence supports a benign effect for A322T, 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 | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -2.252 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.9 | 0.22 | Likely Benign | 0.40 | Likely Benign | -0.52 | Ambiguous | 0.112 | Likely Benign | 0.20 | Neutral | 0.010 | Benign | 0.005 | Benign | 1.95 | Pathogenic | 0.73 | Tolerated | 0.1367 | 0.6432 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2008C>G | L670V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L670V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign. Only ESM1b predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta remains uncertain. Taken together, the overwhelming majority of evidence supports a benign interpretation, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -9.829 | Likely Pathogenic | 0.113 | Likely Benign | Likely Benign | 1.45 | Ambiguous | 0.1 | 1.05 | Ambiguous | 1.25 | Ambiguous | 0.15 | Likely Benign | 0.025 | Likely Benign | -0.60 | Neutral | 0.127 | Benign | 0.023 | Benign | 3.67 | Benign | 0.74 | Tolerated | 0.1558 | 0.4108 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| 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.2338T>G | S780A 2D AIThe SynGAP1 missense variant S780A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S780A is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -5.627 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.40 | Neutral | 0.798 | Possibly Damaging | 0.340 | Benign | 2.69 | Benign | 0.74 | Tolerated | 0.4936 | 0.5522 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2464A>T | T822S 2D AIThe SynGAP1 missense variant T822S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T822S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -1.710 | Likely Benign | 0.655 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -0.54 | Neutral | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 3.08 | Benign | 0.74 | Tolerated | 0.3794 | 0.4547 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2737A>T | T913S 2D AIThe SynGAP1 missense variant T913S is not reported 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 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 computational evidence points to a benign effect, 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 | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -2.636 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.129 | Likely Benign | -0.74 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.80 | Benign | 0.74 | Tolerated | 0.3541 | 0.5147 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2795T>A | F932Y 2D AIThe SynGAP1 missense variant F932Y is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. When predictions are grouped by agreement, the benign‑predicating tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter this balance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta data are unavailable. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.989197 | Binding | 0.293 | 0.858 | 0.500 | -5.248 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.180 | Likely Benign | 1.58 | Neutral | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 3.13 | Benign | 0.74 | Tolerated | 0.1473 | 0.2003 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3112A>T | T1038S 2D AIThe SynGAP1 missense variant T1038S 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. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, 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 | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.693 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.17 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.98 | Benign | 0.74 | Tolerated | 0.2879 | 0.4035 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3113C>G | T1038S 2D AIThe SynGAP1 missense variant T1038S 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. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, 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 | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.693 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.17 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.98 | Benign | 0.74 | Tolerated | 0.2879 | 0.4035 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3376G>A | G1126S 2D AIThe SynGAP1 missense variant G1126S 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1126S, 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 | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -5.004 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.268 | Likely Benign | -0.28 | Neutral | 0.611 | Possibly Damaging | 0.171 | Benign | 4.78 | Benign | 0.74 | Tolerated | 0.2509 | 0.5300 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3427A>T | T1143S 2D AIThe SynGAP1 missense variant T1143S 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 reinforce this view: 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 T1143S is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -2.427 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.34 | Neutral | 0.573 | Possibly Damaging | 0.230 | Benign | 2.76 | Benign | 0.74 | Tolerated | 0.2810 | 0.3640 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1301T>C | V434A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V434A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; FoldX and AlphaMissense‑Default are 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 pathogenic. Overall, the majority of evidence points to a pathogenic 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 | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.531 | Likely Pathogenic | 0.441 | Ambiguous | Likely Benign | 1.72 | Ambiguous | 0.0 | 2.51 | Destabilizing | 2.12 | Destabilizing | 1.00 | Destabilizing | 0.238 | Likely Benign | -2.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.75 | Tolerated | 0.2338 | 0.2292 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.2617A>G | S873G 2D AIThe SynGAP1 missense variant S873G is catalogued in gnomAD (ID 6‑33443169‑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 report 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, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also 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 (none is reported). 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 | 6-33443169-A-G | 4 | 2.48e-6 | -5.702 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -1.88 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0.2897 | 0.5270 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2900G>T | R967L 2D AIThe SynGAP1 missense variant R967L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443452‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for R967L, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.974374 | Disordered | 0.969686 | Binding | 0.340 | 0.888 | 0.750 | Uncertain | 1 | 6-33443452-G-T | 1 | 6.20e-7 | -3.496 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.99 | Neutral | 0.959 | Probably Damaging | 0.586 | Possibly Damaging | 4.15 | Benign | 0.75 | Tolerated | 4.32 | 2 | 0.1964 | 0.5093 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||
| c.3016T>A | Y1006N 2D  AIThe SynGAP1 missense variant Y1006N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default 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 show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -4.238 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.118 | Likely Benign | -0.75 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.75 | Tolerated | 0.2168 | 0.1094 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3227T>C | L1076S 2D  AIThe SynGAP1 missense variant L1076S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes); and Foldetta results are unavailable. Consequently, the evidence is evenly split between benign and pathogenic predictions. The variant is therefore most likely of uncertain significance, 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. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -2.975 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.225 | Likely Benign | 0.55 | Neutral | 0.999 | Probably Damaging | 0.983 | Probably Damaging | 2.43 | Pathogenic | 0.75 | Tolerated | 0.3045 | 0.1178 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.382C>G | P128A 2D AIThe SynGAP1 missense variant P128A 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, 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. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for P128A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -3.677 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.64 | Neutral | 0.580 | Possibly Damaging | 0.140 | Benign | 4.21 | Benign | 0.75 | Tolerated | 0.3890 | 0.3353 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3952C>G | L1318V 2D AIThe SynGAP1 missense variant L1318V is catalogued in gnomAD (ID 6‑33451826‑C‑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, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar record, which contains no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451826-C-G | 1 | 6.31e-7 | -3.938 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.58 | Neutral | 0.113 | Benign | 0.028 | Benign | 4.08 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0.1861 | 0.3027 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.484C>A | R162S 2D  AIThe SynGAP1 missense variant R162S is not reported 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, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). AlphaMissense‑Optimized is currently Uncertain, and no Foldetta stability result is available. Overall, the majority of high‑accuracy and consensus predictions indicate a benign impact. 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. | Likely Benign | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -1.395 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | -0.24 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.14 | Benign | 0.75 | Tolerated | 0.3080 | 0.4974 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.1730C>A | A577E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A577E missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and SIFT, whereas those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain; Rosetta and premPS are inconclusive. Overall, the majority of evaluated tools (five pathogenic vs. four benign) and the SGM‑Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -9.607 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.72 | Ambiguous | 0.51 | Ambiguous | 0.62 | Ambiguous | 0.419 | Likely Benign | -1.91 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.12 | Pathogenic | 0.76 | Tolerated | 0.1487 | 0.1799 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1831A>C | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this 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 | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | 0.229 | Likely Benign | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 0.1130 | 0.3547 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1831A>T | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence points to a benign impact for M611L, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | 0.229 | Likely Benign | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 0.1130 | 0.3547 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.2098C>G | L700V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, protein‑stability methods predict a deleterious impact: FoldX and Rosetta both score the variant as pathogenic, and the combined Foldetta analysis (FoldX‑MD + Rosetta) also reports a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta remains pathogenic. Overall, the majority of predictions support a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -3.703 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 2.52 | Destabilizing | 0.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | 0.13 | Likely Benign | 0.056 | Likely Benign | 0.37 | Neutral | 0.003 | Benign | 0.005 | Benign | 3.46 | Benign | 0.76 | Tolerated | 0.1424 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2666G>C | G889A 2D AIThe SynGAP1 missense variant G889A is listed in gnomAD (6‑33443218‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome, representing a single dissenting signal. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | 6-33443218-G-C | 1 | 6.20e-7 | -4.580 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.49 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.47 | Pathogenic | 0.76 | Tolerated | 4.32 | 4 | 0.3838 | 0.4902 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.943A>C | N315H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N315H 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 (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -6.374 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.29 | Likely Benign | 0.2 | 0.22 | Likely Benign | 0.26 | Likely Benign | 0.28 | Likely Benign | 0.258 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.91 | Pathogenic | 0.76 | Tolerated | 0.1608 | 0.7296 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.1108G>A | G370S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438013‑G‑A). 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 (which is “Likely Benign”). Tools that predict a pathogenic effect are FoldX and FATHMM. Predictions that are inconclusive are Rosetta and Foldetta. High‑accuracy methods give a benign signal: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign; Foldetta 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. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | Uncertain | 2 | 6-33438013-G-A | 15 | 9.31e-6 | -3.533 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 2.83 | Destabilizing | 2.0 | 1.05 | Ambiguous | 1.94 | Ambiguous | -0.02 | Likely Benign | 0.282 | Likely Benign | 0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.77 | Tolerated | 3.42 | 19 | 0.2664 | 0.5086 | 1 | 0 | -0.4 | 30.03 | 196.6 | -49.6 | 0.9 | 2.2 | -0.1 | 0.4 | Uncertain | Gly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn. | ||||||||||||||
| c.2493G>C | E831D 2D AIThe SynGAP1 missense variant E831D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443045‑G‑C). 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 reports a pathogenic or likely‑pathogenic outcome. Grouping by agreement, the benign‑predicting tools comprise the entire set, while no pathogenic predictions are present. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign classification. Foldetta results are unavailable. Overall, the computational evidence strongly supports 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 | 0.626927 | Disordered | 0.617732 | Binding | 0.319 | 0.874 | 0.375 | Uncertain | 1 | 6-33443045-G-C | 1 | 6.19e-7 | -3.055 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 1.23 | Neutral | 0.002 | Benign | 0.002 | Benign | 2.64 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.1537 | 0.4530 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||
| c.2493G>T | E831D 2D AIThe SynGAP1 missense variant E831D is not reported in ClinVar and is absent from gnomAD. All available 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available. Based on the consensus of all predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none exists). 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 | -3.055 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 1.23 | Neutral | 0.002 | Benign | 0.002 | Benign | 2.64 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.1537 | 0.4530 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3041G>A | G1014D 2D AIThe SynGAP1 missense variant G1014D is catalogued in gnomAD (6‑33443593‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1014D, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | 6-33443593-G-A | -4.462 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.029 | Likely Benign | -1.39 | Neutral | 0.818 | Possibly Damaging | 0.381 | Benign | 2.74 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.2003 | 0.2942 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3358G>A | G1120S 2D AIThe SynGAP1 missense variant G1120S 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 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, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that G1120S 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 | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -4.959 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.286 | Likely Benign | -0.27 | Neutral | 0.451 | Benign | 0.209 | Benign | 3.69 | Benign | 0.77 | Tolerated | 0.2515 | 0.5311 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.1096A>T | T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.273 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.53 | Ambiguous | 0.27 | Likely Benign | 0.058 | Likely Benign | 0.00 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.73 | Pathogenic | 0.78 | Tolerated | 0.3549 | 0.4878 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1097C>G | T366S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -3.273 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.53 | Ambiguous | 0.27 | Likely Benign | 0.051 | Likely Benign | 0.00 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.73 | Pathogenic | 0.78 | Tolerated | 0.3549 | 0.4878 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2113A>C | K705Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K705Q missense variant (ClinVar ID 3699560.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (variant ID 6‑33441372‑A‑C). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (benign)—also yields a benign classification; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence supports a benign impact for K705Q, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | Uncertain | 1 | 6-33441372-A-C | 1 | 6.20e-7 | -5.787 | Likely Benign | 0.436 | Ambiguous | Likely Benign | -0.10 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.12 | Likely Benign | -0.02 | Likely Benign | 0.142 | Likely Benign | -0.24 | Neutral | 0.997 | Probably Damaging | 0.969 | Probably Damaging | 3.42 | Benign | 0.78 | Tolerated | 3.47 | 10 | 0.3063 | 0.1014 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||
| c.2431C>T | P811S 2D AIThe SynGAP1 missense variant P811S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not contribute to the evidence. Overall, the preponderance of evidence points to a benign effect for P811S, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -4.733 | Likely Benign | 0.474 | Ambiguous | Likely Benign | 0.128 | Likely Benign | -1.28 | Neutral | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.79 | Benign | 0.78 | Tolerated | 0.3656 | 0.5960 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2692T>A | S898T 2D AIThe SynGAP1 missense variant S898T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.910 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.33 | Neutral | 0.992 | Probably Damaging | 0.814 | Possibly Damaging | 2.50 | Benign | 0.78 | Tolerated | 0.1833 | 0.6209 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3094C>G | L1032V 2D AIThe SynGAP1 missense variant L1032V 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 polyPhen‑2 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 likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for the variant, 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -4.123 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.16 | Neutral | 0.889 | Possibly Damaging | 0.514 | Possibly Damaging | 2.78 | Benign | 0.78 | Tolerated | 0.1637 | 0.4353 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.370G>A | A124T 2D AIThe SynGAP1 missense variant A124T is reported in gnomAD (6-33432235‑G‑A) 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, 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 predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | 6-33432235-G-A | 1 | 6.20e-7 | -3.551 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.26 | Neutral | 0.734 | Possibly Damaging | 0.187 | Benign | 4.17 | Benign | 0.78 | Tolerated | 3.61 | 5 | 0.1828 | 0.7680 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.484C>G | R162G 2D  AIThe SynGAP1 missense variant R162G is listed in ClinVar (ID 2703066.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of predictions support a benign impact, 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 | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Uncertain | 1 | -6.985 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -0.73 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.09 | Benign | 0.78 | Tolerated | 3.74 | 4 | 0.3562 | 0.4308 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.1109G>C | G370A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from FoldX, Foldetta, and FATHMM, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicating a likely benign outcome, and Foldetta suggesting a pathogenic impact via combined FoldX‑MD and Rosetta stability analysis. Overall, the majority of evidence points to a benign effect, with only a minority of tools predicting pathogenicity. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -3.334 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 1.3 | 1.62 | Ambiguous | 2.03 | Destabilizing | -0.14 | Likely Benign | 0.304 | Likely Benign | 0.54 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.79 | Tolerated | 0.3883 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2336G>C | S779T 2D AIThe SynGAP1 missense variant S779T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the consensus of available predictions points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.458 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -0.71 | Neutral | 0.611 | Possibly Damaging | 0.396 | Benign | 2.34 | Pathogenic | 0.79 | Tolerated | 0.1491 | 0.6392 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2645G>C | G882A 2D AIThe SynGAP1 missense variant G882A 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 predict benign, whereas only FATHMM predicts 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 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 | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -3.876 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.05 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.14 | Pathogenic | 0.79 | Tolerated | 0.3345 | 0.5268 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2687G>C | G896A 2D AIThe SynGAP1 missense variant G896A is not reported 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 unavailable. Overall, the majority of evidence points to a benign effect, and there is no conflict with ClinVar status because no ClinVar claim exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -3.562 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.95 | Neutral | 0.561 | Possibly Damaging | 0.139 | Benign | 2.54 | Benign | 0.79 | Tolerated | 0.3799 | 0.4963 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1729G>T | A577S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -4.417 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.60 | Ambiguous | 0.35 | Likely Benign | 0.05 | Likely Benign | 0.342 | Likely Benign | -0.30 | Neutral | 0.981 | Probably Damaging | 0.992 | Probably Damaging | -1.24 | Pathogenic | 0.80 | Tolerated | 0.2763 | 0.5056 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2893C>A | H965N 2D AIThe SynGAP1 missense variant H965N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Across the available in‑silico predictors, the majority (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a benign effect, while no tool predicts pathogenicity. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.978700 | Binding | 0.342 | 0.882 | 0.750 | -7.605 | In-Between | 0.082 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.50 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.09 | Benign | 0.80 | Tolerated | 0.2360 | 0.3838 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2927T>A | F976Y 2D AIThe SynGAP1 missense variant F976Y is not reported 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 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -3.902 | Likely Benign | 0.225 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.50 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 4.11 | Benign | 0.80 | Tolerated | 0.1942 | 0.2257 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.967C>G | L323V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L323V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic predictions (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Benign. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | -3.483 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 2.18 | Destabilizing | 0.3 | 2.22 | Destabilizing | 2.20 | Destabilizing | 0.17 | Likely Benign | 0.227 | Likely Benign | 0.19 | Neutral | 0.898 | Possibly Damaging | 0.472 | Possibly Damaging | 0.80 | Pathogenic | 0.80 | Tolerated | 0.1277 | 0.2656 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1940G>C | G647A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Taken together, the overwhelming majority of evidence indicates a benign effect for G647A, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | -0.266 | Likely Benign | 0.078 | Likely Benign | Likely Benign | -0.18 | Likely Benign | 0.0 | -0.99 | Ambiguous | -0.59 | Ambiguous | -0.69 | Ambiguous | 0.037 | Likely Benign | 0.48 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.55 | Benign | 0.81 | Tolerated | 0.3558 | 0.4136 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2317A>C | M773L 2D AIThe SynGAP1 missense variant M773L 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -3.458 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.75 | Neutral | 0.038 | Benign | 0.137 | Benign | 4.29 | Benign | 0.81 | Tolerated | 0.1517 | 0.3529 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2317A>T | M773L 2D AIThe SynGAP1 missense variant M773L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. 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 not available. Overall, the consensus of all available predictions points to a benign impact, and this is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -3.458 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.75 | Neutral | 0.038 | Benign | 0.137 | Benign | 4.29 | Benign | 0.81 | Tolerated | 0.1517 | 0.3529 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2689T>G | S897A 2D AIThe SynGAP1 missense variant S897A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—including REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. 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 | 0.699094 | Disordered | 0.418474 | Uncertain | 0.292 | 0.928 | 0.500 | -3.959 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.48 | Neutral | 0.288 | Benign | 0.208 | Benign | 2.71 | Benign | 0.81 | Tolerated | 0.4539 | 0.5684 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| 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.2881C>A | H961N 2D AIThe SynGAP1 missense variant H961N 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, 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 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 H961N 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 | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | -8.561 | Likely Pathogenic | 0.096 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.32 | Neutral | 0.069 | Benign | 0.036 | Benign | 4.17 | Benign | 0.81 | Tolerated | 0.2074 | 0.3695 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2995T>G | S999A 2D AIThe SynGAP1 missense variant S999A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, 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 any ClinVar pathogenic annotation. 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 | -3.719 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.83 | Neutral | 0.005 | Benign | 0.016 | Benign | 2.71 | Benign | 0.81 | Tolerated | 0.4516 | 0.5434 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2998A>G | I1000V 2D AIThe SynGAP1 missense variant I1000V is listed in ClinVar (ID 2572013.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that assess evolutionary conservation and structural impact (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default) all converge on a benign outcome. No tool in the dataset predicts pathogenicity. High‑accuracy predictors reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | Uncertain | 2 | -4.102 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.20 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.76 | Benign | 0.81 | Tolerated | 4.32 | 4 | 0.1220 | 0.3404 | 3 | 4 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3109A>C | I1037L 2D AIThe SynGAP1 missense variant I1037L is not reported in ClinVar and is absent from gnomAD, indicating no known clinical or population evidence. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: 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 I1037L 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 | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -2.563 | Likely Benign | 0.448 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -0.46 | Neutral | 0.421 | Benign | 0.128 | Benign | 2.82 | Benign | 0.81 | Tolerated | 0.0939 | 0.4302 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.458C>A | T153N 2D AIThe SynGAP1 missense variant T153N is listed in ClinVar (ID 984906.0) with an “Uncertain” status and is not reported in 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 (HumDiv and HumVar) predict pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. 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 | Conflicting | 3 | -0.739 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.88 | Neutral | 0.888 | Possibly Damaging | 0.537 | Possibly Damaging | 4.23 | Benign | 0.81 | Tolerated | 3.61 | 5 | 0.1313 | 0.3363 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||
| c.609T>A | D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy 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 | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -4.067 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.08 | Likely Benign | 0.09 | Likely Benign | -0.07 | Likely Benign | 0.152 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 4.15 | Benign | 0.81 | Tolerated | 0.0975 | 0.4189 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.609T>G | D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy 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 | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -4.067 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.08 | Likely Benign | 0.09 | Likely Benign | -0.07 | Likely Benign | 0.152 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 4.15 | Benign | 0.81 | Tolerated | 0.0975 | 0.4189 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2101C>G | P701A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these classify the substitution as benign. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -6.836 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 1.35 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.79 | Ambiguous | -0.16 | Likely Benign | 0.058 | Likely Benign | -0.55 | Neutral | 0.002 | Benign | 0.011 | Benign | 3.50 | Benign | 0.82 | Tolerated | 0.3143 | 0.3765 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.2426G>C | S809T 2D AIThe SynGAP1 missense variant S809T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -3.865 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.68 | Neutral | 0.003 | Benign | 0.010 | Benign | 2.95 | Benign | 0.82 | Tolerated | 0.1430 | 0.6617 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2711T>G | M904R 2D  AIThe SynGAP1 missense variant M904R 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for M904R, 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 | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -1.238 | Likely Benign | 0.693 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -0.81 | Neutral | 0.468 | Possibly Damaging | 0.206 | Benign | 2.76 | Benign | 0.82 | Tolerated | 0.1742 | 0.1318 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2813G>C | G938A 2D AIThe SynGAP1 missense variant G938A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta’s protein‑folding stability analysis is not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.068 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.41 | Neutral | 0.979 | Probably Damaging | 0.821 | Possibly Damaging | 2.80 | Benign | 0.82 | Tolerated | 0.3462 | 0.4948 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1427T>G | F476C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476C is catalogued in gnomAD (ID 6‑33438459‑T‑G) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. 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, seven tools predict pathogenicity versus six predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | 6-33438459-T-G | -9.270 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 2.05 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.34 | Destabilizing | -0.30 | Likely Benign | 0.280 | Likely Benign | 2.69 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.46 | Benign | 0.83 | Tolerated | 3.40 | 22 | 0.2051 | 0.1251 | -2 | -4 | -0.3 | -44.04 | |||||||||||||||||||||||||||
| c.2281C>G | R761G 2D AIThe SynGAP1 missense variant R761G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score it as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no contradictory Foldetta data. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation; there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | -4.453 | Likely Benign | 0.427 | Ambiguous | Likely Benign | 0.220 | Likely Benign | -2.07 | Neutral | 0.992 | Probably Damaging | 0.900 | Possibly Damaging | 2.70 | Benign | 0.83 | Tolerated | 0.3333 | 0.3217 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2441C>T | A814V 2D AIThe SynGAP1 missense variant A814V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available, so these do not influence the overall inference. Overall, the preponderance of evidence points to a benign effect for A814V, 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 | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -4.147 | Likely Benign | 0.374 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -0.14 | Neutral | 0.811 | Possibly Damaging | 0.489 | Possibly Damaging | 2.71 | Benign | 0.83 | Tolerated | 0.1088 | 0.6197 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| c.2699C>G | T900R 2D AIThe SynGAP1 missense variant T900R is not reported 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, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts 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 computational 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 | 0.675549 | Disordered | 0.465347 | Uncertain | 0.289 | 0.924 | 0.375 | -3.340 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | 0.34 | Neutral | 0.782 | Possibly Damaging | 0.530 | Possibly Damaging | 2.68 | Benign | 0.83 | Tolerated | 0.1027 | 0.2851 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.346T>G | Y116D 2D AIThe SynGAP1 missense variant Y116D is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, 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 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 consensus of available predictions strongly suggests that Y116D 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 | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | 0.542 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.302 | Likely Benign | -0.14 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.24 | Benign | 0.83 | Tolerated | 0.4603 | 0.0545 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.1187G>C | G396A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.655 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.7 | 1.90 | Ambiguous | 1.82 | Ambiguous | 0.41 | Likely Benign | 0.274 | Likely Benign | -1.28 | Neutral | 0.062 | Benign | 0.024 | Benign | 3.93 | Benign | 0.84 | Tolerated | 0.3846 | 0.5255 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1229G>C | S410T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Foldetta, SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and premPS. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. **Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -6.559 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.32 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.42 | Likely Benign | 0.00 | Likely Benign | 0.066 | Likely Benign | -0.78 | Neutral | 0.080 | Benign | 0.026 | Benign | 4.24 | Benign | 0.84 | Tolerated | 0.1371 | 0.7159 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.2155A>G | N719D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719D 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, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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 individual predictors (seven benign vs. four pathogenic) support a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -9.016 | Likely Pathogenic | 0.416 | Ambiguous | Likely Benign | -0.03 | Likely Benign | 0.0 | 0.64 | Ambiguous | 0.31 | Likely Benign | 0.46 | Likely Benign | 0.106 | Likely Benign | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.75 | Benign | 0.84 | Tolerated | 0.1581 | 0.2345 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.2338T>A | S780T 2D AIThe SynGAP1 missense variant S780T is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -4.911 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.63 | Neutral | 0.951 | Possibly Damaging | 0.614 | Possibly Damaging | 2.66 | Benign | 0.84 | Tolerated | 0.1445 | 0.6631 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>G | L1028R 2D AIThe SynGAP1 missense variant L1028R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.204 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.167 | Likely Benign | -0.24 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 2.75 | Benign | 0.84 | Tolerated | 0.1328 | 0.1603 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3248A>G | K1083R 2D AIThe SynGAP1 missense variant K1083R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -2.212 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.06 | Benign | 0.84 | Tolerated | 0.5053 | 0.1903 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3502A>G | I1168V 2D AIThe SynGAP1 missense variant I1168V is listed in ClinVar (ID 936001.0) 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this consensus does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | Uncertain | 1 | -3.263 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.363 | Likely Benign | -0.14 | Neutral | 0.876 | Possibly Damaging | 0.643 | Possibly Damaging | 5.47 | Benign | 0.84 | Tolerated | 3.88 | 3 | 0.1339 | 0.4374 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.613A>G | I205V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the consensus of all 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 | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -2.232 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.0 | -0.18 | Likely Benign | 0.14 | Likely Benign | 0.11 | Likely Benign | 0.113 | Likely Benign | -0.11 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.20 | Benign | 0.84 | Tolerated | 0.0897 | 0.2791 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| 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.2510T>A | V837D 2D  AIThe SynGAP1 missense variant V837D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -5.712 | Likely Benign | 0.785 | Likely Pathogenic | Ambiguous | 0.127 | Likely Benign | -0.51 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.85 | Tolerated | 0.1415 | 0.0902 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2569A>G | S857G 2D AIThe SynGAP1 missense variant S857G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S857G, 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 | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -4.316 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.57 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 4.10 | Benign | 0.85 | Tolerated | 0.2963 | 0.5644 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| 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.385T>A | S129T 2D AIThe SynGAP1 missense variant S129T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, 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 any ClinVar pathogenic annotation. 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 | -4.296 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.12 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.14 | Benign | 0.85 | Tolerated | 0.1251 | 0.5794 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.651G>C | E217D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E217D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change as benign. The only inconclusive result comes from AlphaMissense‑Default, which is listed as uncertain. High‑accuracy assessments corroborate this benign profile: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign outcome. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -2.268 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.3 | -0.07 | Likely Benign | 0.09 | Likely Benign | -0.34 | Likely Benign | 0.276 | Likely Benign | 0.66 | Neutral | 0.014 | Benign | 0.007 | Benign | 5.85 | Benign | 0.85 | Tolerated | 3.41 | 13 | 0.2066 | 0.5976 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.651G>T | E217D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E217D is present in gnomAD (6‑33435293‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta all report benign or benign‑like outcomes. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized indicates benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports benign. AlphaMissense‑Default remains uncertain and is treated as unavailable. Overall, the evidence strongly supports a benign effect for E217D, 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 | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435293-G-T | 1 | 6.20e-7 | -2.268 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.3 | -0.07 | Likely Benign | 0.09 | Likely Benign | -0.34 | Likely Benign | 0.276 | Likely Benign | 0.66 | Neutral | 0.014 | Benign | 0.007 | Benign | 5.85 | Benign | 0.85 | Tolerated | 3.41 | 13 | 0.2066 | 0.5976 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||
| c.892C>T | P298S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298S is listed in ClinVar as Benign (ClinVar ID 2965590.0) and is present in gnomAD (ID 6‑33437797‑C‑T). 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, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. No evidence from FoldX, Rosetta, or premPS is available to support either outcome. Overall, the majority of predictions support a benign impact, aligning with the ClinVar designation. Thus, the variant is most likely benign and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | Benign | 1 | 6-33437797-C-T | 5 | 3.10e-6 | -6.342 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 1.38 | Ambiguous | 0.2 | 1.41 | Ambiguous | 1.40 | Ambiguous | 0.58 | Ambiguous | 0.189 | Likely Benign | -1.20 | Neutral | 0.991 | Probably Damaging | 0.898 | Possibly Damaging | 2.03 | Pathogenic | 0.85 | Tolerated | 3.39 | 20 | 0.3678 | 0.5855 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||
| c.898T>A | S300T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM 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 is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -4.648 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.1 | -0.30 | Likely Benign | 0.28 | Likely Benign | -0.33 | Likely Benign | 0.056 | Likely Benign | 0.50 | Neutral | 0.003 | Benign | 0.002 | Benign | 1.94 | Pathogenic | 0.85 | Tolerated | 0.1409 | 0.6428 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1039A>T | T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.104 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 0.3205 | 0.4707 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1040C>G | T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.054 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 0.3205 | 0.4707 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1195G>T | A399S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect, while FoldX, Rosetta, and Foldetta are inconclusive. Grouping by agreement, all available predictors fall into the benign category; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, whereas Foldetta’s stability analysis remains uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -4.256 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.89 | Ambiguous | -0.33 | Likely Benign | 0.161 | Likely Benign | 0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.65 | Benign | 0.86 | Tolerated | 0.2494 | 0.4897 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1519A>C | K507Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta, premPS, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -7.698 | In-Between | 0.180 | Likely Benign | Likely Benign | 0.28 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.21 | Likely Benign | -0.52 | Ambiguous | 0.443 | Likely Benign | 0.22 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.86 | Tolerated | 0.2952 | 0.0713 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.2333A>G | N778S 2D AIThe SynGAP1 missense variant N778S is reported in gnomAD (ID 6‑33442491‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and HumVar—predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442491-A-G | 1 | 1.28e-6 | -2.711 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.61 | Neutral | 0.843 | Possibly Damaging | 0.893 | Possibly Damaging | 4.32 | Benign | 0.86 | Tolerated | 3.64 | 6 | 0.4285 | 0.6890 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||||
| c.2986C>G | P996A 2D AIThe SynGAP1 missense variant P996A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion 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 | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -4.596 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.40 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.86 | Tolerated | 0.3242 | 0.4961 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3043A>T | T1015S 2D AIThe SynGAP1 missense variant T1015S 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -2.561 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.61 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.70 | Benign | 0.86 | Tolerated | 0.3545 | 0.4232 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3044C>G | T1015S 2D AIThe SynGAP1 missense variant T1015S 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -2.561 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.61 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.70 | Benign | 0.86 | Tolerated | 0.3545 | 0.4232 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3509G>A | S1170N 2D AIThe SynGAP1 missense variant S1170N is reported in gnomAD (6‑33444544‑G‑A) 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). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. AlphaMissense‑Default is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM‑Consensus both indicate a benign outcome, while the absence of a Foldetta result leaves that aspect unresolved. Overall, the majority of evidence points to a benign effect for S1170N, 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 | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | 6-33444544-G-A | 1 | 6.20e-7 | -3.705 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.342 | Likely Benign | -0.18 | Neutral | 0.992 | Probably Damaging | 0.925 | Probably Damaging | 5.39 | Benign | 0.86 | Tolerated | 4.32 | 4 | 0.1132 | 0.4238 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||
| c.2317A>G | M773V 2D AIThe SynGAP1 missense variant M773V has no ClinVar entry and is not reported in gnomAD. 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 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 computational evidence indicates that M773V 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.353 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.70 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.30 | Benign | 0.87 | Tolerated | 0.3145 | 0.3081 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.526A>C | S176R 2D AIThe SynGAP1 missense variant S176R 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, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized 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 show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.247 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.528C>A | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and 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 | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.528C>G | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and 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 | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| 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.1993T>A | Y665N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y665N variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of conventional predictors lean toward a benign impact, and this assessment does not contradict ClinVar status (none). Thus, the variant is most likely benign based on the prevailing predictions. 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 | -11.189 | Likely Pathogenic | 0.470 | Ambiguous | Likely Benign | 1.11 | Ambiguous | 0.1 | 1.43 | Ambiguous | 1.27 | Ambiguous | 0.50 | Likely Benign | 0.219 | Likely Benign | -3.03 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.50 | Benign | 0.88 | Tolerated | 0.1929 | 0.0573 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||
| c.2341A>C | M781L 2D AIThe SynGAP1 missense variant M781L 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.334 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.83 | Benign | 0.88 | Tolerated | 0.1530 | 0.3669 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2341A>T | M781L 2D AIThe SynGAP1 missense variant M781L 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 predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: 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 not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this prediction is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.334 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.83 | Benign | 0.88 | Tolerated | 0.1530 | 0.3669 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3035C>G | P1012R 2D  AIThe SynGAP1 missense variant P1012R 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 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 | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.413 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 1.24 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.89 | Benign | 0.88 | Tolerated | 0.1339 | 0.3083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3086A>G | Q1029R 2D AIThe SynGAP1 missense variant Q1029R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and 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, and the SGM‑Consensus also indicates likely benign; 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 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.437 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.073 | Likely Benign | -0.72 | Neutral | 0.961 | Probably Damaging | 0.677 | Possibly Damaging | 2.73 | Benign | 0.88 | Tolerated | 0.1377 | 0.2420 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3215A>G | K1072R 2D AIThe SynGAP1 missense variant K1072R is reported in gnomAD (ID 6‑33443767‑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 (HumDiv and HumVar) predict it to be pathogenic. 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 data are available, so folding‑stability evidence is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with 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 | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | 6-33443767-A-G | 1 | 6.23e-7 | -2.458 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.15 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.16 | Benign | 0.88 | Tolerated | 3.77 | 5 | 0.4655 | 0.2061 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||
| c.3293G>C | S1098T 2D AIThe SynGAP1 missense variant S1098T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, 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 | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -4.144 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.18 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.88 | Tolerated | 0.1706 | 0.6653 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3901C>G | P1301A 2D AIThe SynGAP1 missense variant P1301A is catalogued in gnomAD (ID 6‑33451775‑C‑G) 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 tolerated or benign. No tool in the dataset 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) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this residue. Overall, the consensus of all available predictions is benign, 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-G | 1 | 6.20e-7 | -4.290 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.66 | Neutral | 0.003 | Benign | 0.012 | Benign | 3.05 | Benign | 0.88 | Tolerated | 3.77 | 5 | 0.2850 | 0.3087 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.1057C>G | L353V 2D AISynGAP1 missense variant L353V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools predicting pathogenicity are FoldX and FATHMM, while Rosetta gives an uncertain result. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the balance of evidence favors a benign effect; 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 | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -2.100 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 3.08 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.28 | Destabilizing | -0.45 | Likely Benign | 0.074 | Likely Benign | 1.54 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.46 | Pathogenic | 0.89 | Tolerated | 0.1567 | 0.3829 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1939G>A | G647S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from Rosetta and premPS, which are treated as unavailable. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the evidence strongly favors a benign classification, and this is consistent with its absence from ClinVar. The variant is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | -2.175 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.05 | Likely Benign | 0.1 | -0.75 | Ambiguous | -0.35 | Likely Benign | -0.56 | Ambiguous | 0.037 | Likely Benign | 0.65 | Neutral | 0.002 | Benign | 0.004 | Benign | 3.48 | Benign | 0.89 | Tolerated | 0.2409 | 0.3959 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2819G>C | G940A 2D AIThe SynGAP1 missense variant G940A 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 any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -5.356 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.64 | Neutral | 0.004 | Benign | 0.012 | Benign | 2.85 | Benign | 0.89 | Tolerated | 0.3627 | 0.4831 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>C | G943A 2D AIThe SynGAP1 missense variant G943A is reported in gnomAD (ID 6‑33443380‑G‑C) but has no ClinVar entry. All available 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 not available. Based on the unanimous benign predictions and lack of ClinVar pathogenicity, the variant is most likely benign and does not contradict any ClinVar status. 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 | 6-33443380-G-C | 3 | 1.86e-6 | -6.684 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.274 | Likely Benign | 0.10 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.87 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0.3415 | 0.4957 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2896C>A | H966N 2D AIThe SynGAP1 missense variant H966N is not reported 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that H966N 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 | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | -7.579 | In-Between | 0.085 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.84 | Neutral | 0.748 | Possibly Damaging | 0.232 | Benign | 4.06 | Benign | 0.89 | Tolerated | 0.2153 | 0.3788 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3004C>G | H1002D 2D AIThe SynGAP1 missense variant H1002D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -6.511 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.218 | Likely Benign | -2.09 | Neutral | 0.891 | Possibly Damaging | 0.673 | Possibly Damaging | 2.75 | Benign | 0.89 | Tolerated | 0.2597 | 0.2335 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3434A>G | N1145S 2D AIThe SynGAP1 missense variant N1145S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33444469‑A‑G). 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 show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign 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 | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | Uncertain | 1 | 6-33444469-A-G | 2 | 1.24e-6 | -0.989 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.308 | Likely Benign | -1.15 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.55 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0.4078 | 0.6708 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||
| c.1240A>C | M414L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. Uncertain predictions come from premPS and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the preponderance of evidence indicates that M414L is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -7.980 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.30 | Likely Benign | 0.64 | Ambiguous | 0.336 | Likely Benign | -2.40 | Neutral | 0.559 | Possibly Damaging | 0.495 | Possibly Damaging | 3.63 | Benign | 0.90 | Tolerated | 0.1323 | 0.4236 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||
| c.1240A>T | M414L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. Uncertain predictions come from premPS and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the preponderance of evidence indicates that M414L is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -7.980 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.30 | Likely Benign | 0.64 | Ambiguous | 0.336 | Likely Benign | -2.40 | Neutral | 0.559 | Possibly Damaging | 0.495 | Possibly Damaging | 3.63 | Benign | 0.90 | Tolerated | 0.1323 | 0.4236 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||
| c.1339G>C | V447L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | 0.180 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 0.0757 | 0.3477 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1427T>A | F476Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts a benign outcome. Overall, the balance of evidence leans toward a benign impact for F476Y, 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 | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -9.707 | Likely Pathogenic | 0.576 | Likely Pathogenic | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.30 | Likely Benign | 0.40 | Likely Benign | 1.10 | Destabilizing | 0.169 | Likely Benign | -1.10 | Neutral | 0.965 | Probably Damaging | 0.919 | Probably Damaging | 3.46 | Benign | 0.90 | Tolerated | 0.1109 | 0.1568 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||
| c.2341A>G | M781V 2D AIThe SynGAP1 missense variant M781V is listed in ClinVar (ID 4746135) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33442893‑A‑G). 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 reports a pathogenic prediction. High‑accuracy assessments corroborate this benign profile: 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, did not provide a result for this variant. Overall, the computational evidence strongly 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | Uncertain | 1 | 6-33442893-A-G | 4 | 2.48e-6 | -2.624 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.174 | Likely Benign | 0.00 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.03 | Benign | 0.90 | Tolerated | 3.64 | 6 | 0.3081 | 0.2705 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||
| c.2683A>G | S895G 2D AIThe SynGAP1 missense variant S895G is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this 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 | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -3.728 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -1.25 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.67 | Benign | 0.90 | Tolerated | 0.2675 | 0.5087 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>G | P954A 2D AIThe SynGAP1 missense variant P954A is not reported 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. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -4.985 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.21 | Neutral | 0.856 | Possibly Damaging | 0.652 | Possibly Damaging | 2.91 | Benign | 0.90 | Tolerated | 0.3103 | 0.5550 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3017A>C | Y1006S 2D AIThe SynGAP1 missense variant Y1006S has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also 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 majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for Y1006S. 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 | -2.522 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.58 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.83 | Benign | 0.90 | Tolerated | 0.4426 | 0.2274 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3418A>T | T1140S 2D AIThe SynGAP1 missense variant T1140S 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 | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -2.805 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.27 | Neutral | 0.025 | Benign | 0.010 | Benign | 3.25 | Benign | 0.91 | Tolerated | 0.3401 | 0.3504 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.358G>A | G120S 2D AIThe SynGAP1 missense variant G120S is reported in gnomAD (variant ID 6-33432223‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly classify the change 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. The high‑accuracy consensus methods 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 predictor, was not available for this variant. Overall, the evidence strongly supports a benign classification, and there is 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 | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | 6-33432223-G-A | 1 | 6.20e-7 | -3.558 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 0.07 | Neutral | 0.020 | Benign | 0.012 | Benign | 4.29 | Benign | 0.91 | Tolerated | 3.61 | 5 | 0.2841 | 0.4713 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3791G>C | G1264A 2D AIThe SynGAP1 missense variant G1264A 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 likewise indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of any ClinVar assertion. 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 | -3.460 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.32 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.79 | Benign | 0.91 | Tolerated | 0.3504 | 0.4220 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3943T>A | W1315R 2D  AIThe SynGAP1 missense variant W1315R is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only AlphaMissense‑Default predicts a pathogenic outcome, representing the sole discordant signal. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools points to a benign effect, 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 0.4317 | 0.0384 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||||
| c.3943T>C | W1315R 2D AIThe SynGAP1 missense variant W1315R is listed in ClinVar (ID 1029092.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available for this variant. Overall, the majority of evidence points to 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | Uncertain | 1 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 0.4317 | 0.0384 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.511G>T | A171S 2D AIThe SynGAP1 missense variant A171S 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 results are unavailable. Based on the collective 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 | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -0.011 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.40 | Neutral | 0.002 | Benign | 0.001 | Benign | 4.33 | Benign | 0.91 | Tolerated | 0.2221 | 0.4383 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.1227G>A | M409I 2D  AISynGAP1 missense variant M409I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default). High‑accuracy assessments reinforce the benign trend: 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. FoldX and Rosetta individually give uncertain results and are treated as unavailable. Overall, the majority of reliable predictors indicate a benign impact for M409I. Thus, the variant is most likely benign, and this conclusion does not contradict the lack of a ClinVar classification. 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 | -3.735 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.8 | -0.79 | Ambiguous | -0.10 | Likely Benign | 0.36 | Likely Benign | 0.162 | Likely Benign | -0.58 | Neutral | 0.579 | Possibly Damaging | 0.663 | Possibly Damaging | 4.22 | Benign | 0.92 | Tolerated | 0.1105 | 0.3358 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1227G>C | M409I 2D AISynGAP1 missense variant M409I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default). High‑accuracy assessments reinforce the benign trend: 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. FoldX and Rosetta individually give uncertain results and are treated as unavailable. Overall, the majority of reliable predictors indicate a benign impact for M409I, 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 | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -3.735 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.8 | -0.79 | Ambiguous | -0.10 | Likely Benign | 0.36 | Likely Benign | 0.162 | Likely Benign | -0.58 | Neutral | 0.579 | Possibly Damaging | 0.663 | Possibly Damaging | 4.22 | Benign | 0.92 | Tolerated | 0.1105 | 0.3358 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1227G>T | M409I 2D AISynGAP1 missense variant M409I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default). High‑accuracy assessments reinforce the benign trend: 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. FoldX and Rosetta individually give uncertain results and are treated as unavailable. Overall, the majority of reliable predictors indicate a benign impact for M409I, 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 | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -3.735 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.8 | -0.79 | Ambiguous | -0.10 | Likely Benign | 0.36 | Likely Benign | 0.162 | Likely Benign | -0.58 | Neutral | 0.579 | Possibly Damaging | 0.663 | Possibly Damaging | 4.22 | Benign | 0.92 | Tolerated | 0.1105 | 0.3358 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1319A>G | N440S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or likely benign. Only FoldX and premPS returned uncertain results, which are treated as unavailable. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -1.753 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.30 | Likely Benign | -0.50 | Ambiguous | 0.104 | Likely Benign | 1.15 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.53 | Benign | 0.92 | Tolerated | 0.2024 | 0.3556 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1492A>C | M498L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498L is not 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. 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. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, 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 | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | 2.556 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.1 | -0.89 | Ambiguous | -0.56 | Ambiguous | -0.53 | Ambiguous | 0.271 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.24 | Pathogenic | 0.92 | Tolerated | 0.1319 | 0.3551 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1492A>T | M498L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M498L is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta, Foldetta, and premPS are inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta remains uncertain. Taken together, the preponderance of evidence indicates that M498L 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. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | Uncertain | 1 | 2.556 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.1 | -0.89 | Ambiguous | -0.56 | Ambiguous | -0.53 | Ambiguous | 0.271 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.24 | Pathogenic | 0.92 | Tolerated | 0.1319 | 0.3551 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||
| c.1563G>C | E521D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E521D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a Benign effect. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -4.963 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.15 | Likely Benign | -0.29 | Likely Benign | 0.227 | Likely Benign | 1.07 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.92 | Tolerated | 0.2026 | 0.3721 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1563G>T | E521D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521D missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome. The high‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign, the SGM‑Consensus 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 preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -4.963 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.15 | Likely Benign | -0.29 | Likely Benign | 0.227 | Likely Benign | 1.07 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.92 | Tolerated | 0.2026 | 0.3721 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2178G>C | R726S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726S 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, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, 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 any ClinVar status (none reported). 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 | -4.780 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.40 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.17 | Likely Benign | -0.16 | Likely Benign | 0.232 | Likely Benign | -0.41 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.66 | Benign | 0.92 | Tolerated | 0.2993 | 0.3956 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||
| c.2178G>T | R726S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726S 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, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, 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 any ClinVar status (none reported). 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 | -4.780 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.40 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.17 | Likely Benign | -0.16 | Likely Benign | 0.232 | Likely Benign | -0.41 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.66 | Benign | 0.92 | Tolerated | 0.2993 | 0.3956 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||
| c.2695A>G | I899V 2D AIThe SynGAP1 missense variant I899V is listed in ClinVar as a benign alteration (ClinVar ID 1003653.0) and is present in the gnomAD database (gnomAD ID 6‑33443247‑A‑G). All evaluated in‑silico predictors classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments further support a benign effect: AlphaMissense‑Optimized reports 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, did not provide a result for this variant. Overall, the computational evidence strongly suggests the variant is benign, consistent with its ClinVar classification. 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 | Benign | 1 | 6-33443247-A-G | 6 | 3.72e-6 | -2.569 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.09 | Neutral | 0.220 | Benign | 0.078 | Benign | 2.75 | Benign | 0.92 | Tolerated | 4.32 | 4 | 0.1169 | 0.2864 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||
| c.2699C>A | T900K 2D AISynGAP1 missense variant T900K has no ClinVar entry and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign), whereas pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports 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 preponderance of evidence points to a benign effect for T900K, 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 | 0.465347 | Uncertain | 0.289 | 0.924 | 0.375 | -4.566 | Likely Benign | 0.721 | Likely Pathogenic | Likely Benign | 0.080 | Likely Benign | -0.64 | Neutral | 0.782 | Possibly Damaging | 0.447 | Possibly Damaging | 2.69 | Benign | 0.92 | Tolerated | 0.1189 | 0.3038 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| 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.3364G>A | G1122S 2D AIThe SynGAP1 missense variant G1122S is listed in ClinVar (ID 643187) as Benign and is present in gnomAD (6‑33443916‑G‑A). Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates Benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign. The Foldetta stability analysis is unavailable for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | Benign/Likely benign | 3 | 6-33443916-G-A | 27 | 1.79e-5 | -4.880 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.189 | Likely Benign | -0.08 | Neutral | 0.022 | Benign | 0.006 | Benign | 4.89 | Benign | 0.92 | Tolerated | 3.77 | 5 | 0.2537 | 0.5111 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.958G>C | V320L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320L (gnomAD ID 6‑33437863‑G‑C) is listed in ClinVar as uncertain. Functional prediction tools show a predominance of benign calls: REVEL, FoldX, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from polyPhen2_HumDiv and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the balance of evidence favors a benign effect for V320L, which is consistent with its ClinVar designation of uncertain significance rather than a pathogenic classification. Based on the aggregate predictions, V320L is most likely benign, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Conflicting | 2 | 6-33437863-G-C | 6 | 3.72e-6 | -6.207 | Likely Benign | 0.362 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | 0.096 | Likely Benign | -1.02 | Neutral | 0.900 | Possibly Damaging | 0.373 | Benign | 1.78 | Pathogenic | 0.92 | Tolerated | 3.38 | 23 | 0.0661 | 0.3863 | 2 | 1 | -0.4 | 14.03 | 245.8 | -10.2 | 0.3 | 0.9 | 0.1 | 0.3 | X | Potentially Benign | The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations. | ||||||||||||||
| 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.2186A>G | N729S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Across the available in‑silico predictors, the majority (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as benign, while Rosetta and Foldetta return uncertain results. No tool predicts pathogenicity. High‑accuracy assessments reinforce this benign trend: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta’s stability prediction is inconclusive. Overall, the computational evidence strongly supports a benign effect, 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 | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | Conflicting | 2 | -1.578 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.14 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.74 | Ambiguous | -0.36 | Likely Benign | 0.063 | Likely Benign | -0.42 | Neutral | 0.221 | Benign | 0.027 | Benign | 3.38 | Benign | 0.93 | Tolerated | 3.59 | 7 | 0.3411 | 0.4854 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||
| c.2720G>C | S907T 2D AIThe SynGAP1 missense variant S907T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -4.794 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.53 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.66 | Benign | 0.93 | Tolerated | 0.1324 | 0.6352 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2896C>G | H966D 2D AIThe SynGAP1 missense variant H966D is listed in gnomAD (ID 6‑33443448‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only two tools predict a damaging outcome—polyPhen‑2 HumDiv and ESM1b—which are outliers relative to the consensus. High‑accuracy assessments confirm the benign trend: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus also indicates a likely benign status. 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 pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | 6-33443448-C-G | 1 | 6.20e-7 | -8.426 | Likely Pathogenic | 0.201 | Likely Benign | Likely Benign | 0.182 | Likely Benign | -1.09 | Neutral | 0.494 | Possibly Damaging | 0.170 | Benign | 4.05 | Benign | 0.93 | Tolerated | 4.32 | 2 | 0.2504 | 0.3066 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.3104C>G | P1035R 2D AIThe SynGAP1 missense variant P1035R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -4.534 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.119 | Likely Benign | 1.07 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.89 | Benign | 0.93 | Tolerated | 0.1424 | 0.4201 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3109A>G | I1037V 2D AIThe SynGAP1 missense variant I1037V 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, 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, 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 I1037V is most likely benign, and this conclusion is not contradicted by ClinVar status. 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 | -2.326 | Likely Benign | 0.461 | Ambiguous | Likely Benign | 0.085 | Likely Benign | -0.09 | Neutral | 0.421 | Benign | 0.128 | Benign | 2.76 | Benign | 0.93 | Tolerated | 0.1229 | 0.3985 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3224A>G | Q1075R 2D AIThe SynGAP1 missense variant Q1075R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign effect, 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 | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -5.039 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -0.37 | Neutral | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 2.72 | Benign | 0.93 | Tolerated | 0.1504 | 0.2650 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>T | T1310M 2D  AIThe SynGAP1 missense variant T1310M is listed in ClinVar (ID 2160201.0) as Benign and is present in gnomAD (gnomAD ID 6‑33451803‑C‑T). All evaluated in‑silico predictors report a benign outcome: 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | Benign | 1 | 6-33451803-C-T | 17 | 1.05e-5 | -4.822 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.1144 | 0.5397 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||||||
| c.3940C>G | P1314A 2D AIThe SynGAP1 missense variant P1314A is catalogued in gnomAD (ID 6‑33451814‑C‑G) 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—returns a benign or likely benign verdict. No pathogenic predictions appear in the dataset, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Taken together, the evidence overwhelmingly supports a benign classification, and this conclusion does not conflict with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451814-C-G | 1 | 6.22e-7 | -3.540 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.23 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.3502 | 0.4441 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.4024G>A | D1342N 2D AIThe SynGAP1 missense variant D1342N is catalogued in gnomAD (ID 6‑33451898‑G‑A) but has no ClinVar submission. 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 tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting 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 stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign classification, 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 | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | 6-33451898-G-A | -3.459 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.29 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.07 | Benign | 0.93 | Tolerated | 4.32 | 4 | 0.1868 | 0.6022 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| c.2122C>G | L708V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the evidence strongly indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -4.361 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 1.59 | Ambiguous | 0.0 | 0.12 | Likely Benign | 0.86 | Ambiguous | -0.02 | Likely Benign | 0.122 | Likely Benign | -0.23 | Neutral | 0.158 | Benign | 0.035 | Benign | 3.35 | Benign | 0.94 | Tolerated | 0.1094 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2600G>C | G867A 2D AIThe SynGAP1 missense variant G867A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -4.638 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.18 | Neutral | 0.990 | Probably Damaging | 0.828 | Possibly Damaging | 2.79 | Benign | 0.94 | Tolerated | 0.3666 | 0.5534 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.3610T>A | S1204T 2D AIThe SynGAP1 missense variant S1204T 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 “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is available). 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 | -5.056 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.292 | Likely Benign | -0.53 | Neutral | 0.826 | Possibly Damaging | 0.551 | Possibly Damaging | 5.42 | Benign | 0.94 | Tolerated | 0.1466 | 0.4510 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.729T>G | I243M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243M has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign”; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -4.305 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.13 | Likely Benign | -0.01 | Likely Benign | 0.474 | Likely Benign | 0.58 | Neutral | 0.985 | Probably Damaging | 0.798 | Possibly Damaging | 5.61 | Benign | 0.94 | Tolerated | 0.0553 | 0.2200 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.2434C>T | P812S 2D AIThe SynGAP1 missense variant P812S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442986‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and no Foldetta stability result is available. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 1 | 6-33442986-C-T | 1 | 6.20e-7 | -5.689 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -0.62 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.89 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.3417 | 0.5699 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.2708G>T | G903V 2D  AIThe SynGAP1 missense variant G903V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default remains 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 balance of evidence (five benign predictions versus three pathogenic predictions, with no conflicting ClinVar annotation) indicates that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant is not currently catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -4.750 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -1.93 | Neutral | 0.997 | Probably Damaging | 0.959 | Probably Damaging | 2.44 | Pathogenic | 0.95 | Tolerated | 0.1269 | 0.4266 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2821C>T | P941S 2D AIThe SynGAP1 missense variant P941S is reported in gnomAD (ID 6‑33443373‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. 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, which evaluates protein‑folding stability via FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of all available predictions indicates that P941S is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-T | 1 | 6.20e-7 | -5.099 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 3.05 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.2759 | 0.5576 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3304G>A | A1102T 2D AIThe SynGAP1 missense variant A1102T is listed in ClinVar (ID 1422927) as Benign and is present in gnomAD (6‑33443856‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic 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 supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | Benign | 1 | 6-33443856-G-A | 11 | 7.17e-6 | -3.540 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.30 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.32 | Pathogenic | 0.95 | Tolerated | 3.77 | 5 | 0.1755 | 0.7699 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3901C>T | P1301S 2D AIThe SynGAP1 missense variant P1301S is not reported in ClinVar and is absent from 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 benign prediction: 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 available result for this variant. Overall, the computational evidence strongly supports 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | -4.537 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 1.84 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.29 | Benign | 0.95 | Tolerated | 0.2799 | 0.3436 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2302G>A | D768N 2D AIThe SynGAP1 missense variant D768N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442460‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | Uncertain | 1 | 6-33442460-G-A | 2 | 2.57e-6 | -6.892 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.048 | Likely Benign | -0.77 | Neutral | 0.106 | Benign | 0.009 | Benign | 4.07 | Benign | 0.96 | Tolerated | 3.64 | 6 | 0.1178 | 0.7843 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||
| c.3859C>T | P1287S 2D AIThe SynGAP1 missense variant P1287S is catalogued in gnomAD (ID 6‑33447907‑C‑T) 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 scores the variant as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” 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 assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | 6-33447907-C-T | -3.258 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.70 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.96 | Benign | 0.96 | Tolerated | 3.77 | 5 | 0.2820 | 0.3566 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.1313C>T | A438V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (gnomAD ID 6‑33438218‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive (Uncertain). Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | 6-33438218-C-T | 3 | 1.86e-6 | 1.405 | Likely Benign | 0.073 | Likely Benign | Likely Benign | -0.36 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.53 | Ambiguous | -1.21 | Stabilizing | 0.046 | Likely Benign | 1.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.45 | Benign | 0.97 | Tolerated | 3.38 | 26 | 0.0904 | 0.5292 | 0 | 0 | 2.4 | 28.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||
| 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.3517A>C | I1173L 2D AIThe SynGAP1 missense variant I1173L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -1.792 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -0.30 | Neutral | 0.152 | Benign | 0.102 | Benign | 5.41 | Benign | 0.97 | Tolerated | 0.0745 | 0.3004 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3940C>A | P1314T 2D AIThe SynGAP1 missense variant P1314T is present in gnomAD (ID 6‑33451814‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; 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—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this is consistent with the lack of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451814-C-A | -4.083 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.26 | Neutral | 0.061 | Benign | 0.045 | Benign | 4.32 | Benign | 0.97 | Tolerated | 3.77 | 5 | 0.1791 | 0.5626 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| 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.2221C>G | P741A 2D AIThe SynGAP1 missense variant P741A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” while Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -3.995 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.33 | Neutral | 0.425 | Benign | 0.136 | Benign | 3.01 | Benign | 0.98 | Tolerated | 0.2942 | 0.3883 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2420A>T | Y807F 2D AIThe SynGAP1 missense variant Y807F is listed in ClinVar (ID 1491782.0) with an “Uncertain” status and is not reported in 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 all return benign scores, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No tool in the set predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four high‑accuracy predictors) is benign. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | Uncertain | 1 | -3.667 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.14 | Neutral | 0.012 | Benign | 0.022 | Benign | 2.92 | Benign | 0.98 | Tolerated | 3.77 | 5 | 0.2485 | 0.2500 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||||||
| 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.3179G>C | G1060A 2D AIThe SynGAP1 missense variant G1060A 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 | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -6.539 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.341 | Likely Benign | 0.30 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.69 | Benign | 0.98 | Tolerated | 0.3335 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3758C>A | A1253E 2D AIThe SynGAP1 missense variant A1253E 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 predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion 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 | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -1.744 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 2.03 | Neutral | 0.301 | Benign | 0.209 | Benign | 3.03 | Benign | 0.98 | Tolerated | 0.0948 | 0.1704 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.991T>A | S331T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331T is 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, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and premPS are inconclusive (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Taken together, the majority of evidence indicates that S331T is most likely benign, and this conclusion does not contradict the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -2.474 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.2 | -0.10 | Likely Benign | 0.25 | Likely Benign | -0.72 | Ambiguous | 0.095 | Likely Benign | 1.13 | Neutral | 0.003 | Benign | 0.002 | Benign | 1.86 | Pathogenic | 0.98 | Tolerated | 0.1505 | 0.4552 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.461G>C | S154T 2D AIThe SynGAP1 missense variant S154T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including 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 | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -5.313 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.32 | Neutral | 0.900 | Possibly Damaging | 0.434 | Benign | 4.13 | Benign | 0.99 | Tolerated | 0.1686 | 0.5099 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1054A>T | T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.670 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.09 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.09 | Likely Benign | -0.01 | Likely Benign | 0.098 | Likely Benign | 0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.81 | Pathogenic | 1.00 | Tolerated | 0.3583 | 0.4880 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1055C>G | T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.670 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.09 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.09 | Likely Benign | -0.01 | Likely Benign | 0.104 | Likely Benign | 0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.81 | Pathogenic | 1.00 | Tolerated | 0.3583 | 0.4880 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1071C>A | H357Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Based on the uniform 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 | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -4.370 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.06 | Likely Benign | 0.2 | -0.03 | Likely Benign | 0.02 | Likely Benign | -0.35 | Likely Benign | 0.025 | Likely Benign | 1.42 | Neutral | 0.013 | Benign | 0.007 | Benign | 4.49 | Benign | 1.00 | Tolerated | 0.1716 | 0.3850 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1071C>G | H357Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H357Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess sequence conservation, structural impact, or functional effect all converge on a benign outcome: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Based on the uniform 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 | C2 | 0.203355 | Structured | 0.399052 | Uncertain | 0.861 | 0.413 | 0.250 | -4.370 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.06 | Likely Benign | 0.2 | -0.03 | Likely Benign | 0.02 | Likely Benign | -0.35 | Likely Benign | 0.025 | Likely Benign | 1.42 | Neutral | 0.013 | Benign | 0.007 | Benign | 4.49 | Benign | 1.00 | Tolerated | 0.1716 | 0.3850 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| 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>G | M409V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409V is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors indicates a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports benign. No conflicting evidence is present. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -4.109 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 1.13 | Ambiguous | 0.2 | -0.25 | Likely Benign | 0.44 | Likely Benign | 0.37 | Likely Benign | 0.163 | Likely Benign | -0.76 | Neutral | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 4.26 | Benign | 1.00 | Tolerated | 0.2706 | 0.4286 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| 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.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.1496G>A | R499K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499K is not reported 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no evidence for either direction. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for R499K, 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 | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 4.366 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 1.37 | Ambiguous | 0.1 | 0.53 | Ambiguous | 0.95 | Ambiguous | -0.77 | Ambiguous | 0.248 | Likely Benign | 1.94 | Neutral | 0.001 | Benign | 0.008 | Benign | -1.03 | Pathogenic | 1.00 | Tolerated | 0.3531 | 0.1881 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||
| c.1501A>G | I501V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501V 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions from FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable. 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 I501V, 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 | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -2.326 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.0 | 0.56 | Ambiguous | 0.75 | Ambiguous | 0.06 | Likely Benign | 0.200 | Likely Benign | 0.20 | Neutral | 0.951 | Possibly Damaging | 0.960 | Probably Damaging | 3.52 | Benign | 1.00 | Tolerated | 0.0985 | 0.2491 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1528A>C | I510L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all 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 | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -2.362 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.2 | -0.05 | Likely Benign | 0.13 | Likely Benign | -1.01 | Stabilizing | 0.338 | Likely Benign | 0.69 | Neutral | 0.016 | Benign | 0.130 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 0.0819 | 0.2461 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1585A>G | I529V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33438828‑A‑G). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. 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, the SGM Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.318242 | Structured | 0.019545 | Uncertain | 0.901 | 0.403 | 0.000 | 6-33438828-A-G | 1 | 6.20e-7 | -2.342 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.18 | Likely Benign | 0.0 | 0.03 | Likely Benign | 0.11 | Likely Benign | 0.36 | Likely Benign | 0.230 | Likely Benign | -0.21 | Neutral | 0.019 | Benign | 0.014 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 3.37 | 35 | 0.1043 | 0.3526 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||
| c.1594A>T | T532S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | 0.616 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.1 | -0.23 | Likely Benign | -0.04 | Likely Benign | -0.10 | Likely Benign | 0.160 | Likely Benign | 0.53 | Neutral | 0.005 | Benign | 0.013 | Benign | -1.22 | Pathogenic | 1.00 | Tolerated | 0.2988 | 0.2866 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1610C>A | A537E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | -5.120 | Likely Benign | 0.450 | Ambiguous | Likely Benign | -0.14 | Likely Benign | 0.1 | 0.00 | Likely Benign | -0.07 | Likely Benign | 0.23 | Likely Benign | 0.378 | Likely Benign | -1.78 | Neutral | 0.987 | Probably Damaging | 0.838 | Possibly Damaging | -1.04 | Pathogenic | 1.00 | Tolerated | 0.1347 | 0.1566 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||
| c.1663G>A | V555I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, Rosetta, 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, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, 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 | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | Uncertain | 1 | -4.544 | Likely Benign | 0.084 | Likely Benign | Likely Benign | -0.82 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.62 | Ambiguous | -0.55 | Ambiguous | 0.253 | Likely Benign | 0.45 | Neutral | 0.002 | Benign | 0.002 | Benign | -1.26 | Pathogenic | 1.00 | Tolerated | 0.0844 | 0.2590 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.1672C>T | H558Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H558Y 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX, premPS, and ESM1b are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign result; and Foldetta also predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.033407 | Structured | 0.011039 | Uncertain | 0.897 | 0.200 | 0.000 | -7.208 | In-Between | 0.187 | Likely Benign | Likely Benign | -0.58 | Ambiguous | 0.0 | -0.36 | Likely Benign | -0.47 | Likely Benign | -0.56 | Ambiguous | 0.359 | Likely Benign | 0.55 | Neutral | 0.019 | Benign | 0.013 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 0.0938 | 0.2363 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.1758C>A | D586E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586E 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, ESM1b, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -3.233 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.23 | Likely Benign | 0.38 | Likely Benign | 0.367 | Likely Benign | -0.12 | Neutral | 0.929 | Possibly Damaging | 0.969 | Probably Damaging | -1.20 | Pathogenic | 1.00 | Tolerated | 0.1304 | 0.5126 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1758C>G | D586E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586E 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -3.233 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.23 | Likely Benign | 0.38 | Likely Benign | 0.367 | Likely Benign | -0.12 | Neutral | 0.929 | Possibly Damaging | 0.969 | Probably Damaging | -1.20 | Pathogenic | 1.00 | Tolerated | 0.1304 | 0.5126 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1853A>G | Q618R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -2.513 | Likely Benign | 0.207 | Likely Benign | Likely Benign | -0.43 | Likely Benign | 0.1 | 0.60 | Ambiguous | 0.09 | Likely Benign | -0.66 | Ambiguous | 0.285 | Likely Benign | 1.22 | Neutral | 0.005 | Benign | 0.009 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 0.1218 | 0.1163 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1909T>G | S637A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, SIFT, polyPhen‑2 (HumDiv and HumVar), REVEL, FoldX, and premPS. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive (Uncertain). Taken together, the overwhelming majority of evidence indicates a benign effect. The variant’s status is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -4.186 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.65 | Ambiguous | 0.22 | Likely Benign | 0.078 | Likely Benign | -0.64 | Neutral | 0.120 | Benign | 0.182 | Benign | 3.41 | Benign | 1.00 | Tolerated | 0.4853 | 0.2996 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1932C>A | D644E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D644E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments confirm a benign impact: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. 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 | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -1.778 | Likely Benign | 0.178 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.1 | -0.51 | Ambiguous | -0.34 | Likely Benign | -0.47 | Likely Benign | 0.132 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.55 | Benign | 1.00 | Tolerated | 0.1528 | 0.6186 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1932C>G | D644E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D644E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments confirm a benign impact: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. 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 | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -1.778 | Likely Benign | 0.178 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.1 | -0.51 | Ambiguous | -0.34 | Likely Benign | -0.47 | Likely Benign | 0.132 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.55 | Benign | 1.00 | Tolerated | 0.1528 | 0.6186 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1934T>A | F645Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools with inconclusive results are FoldX (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, the SGM‑Consensus indicating Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicting Benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as the variant is not currently classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -3.544 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.2 | 0.21 | Likely Benign | 0.37 | Likely Benign | -0.61 | Ambiguous | 0.141 | Likely Benign | 2.40 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.61 | Benign | 1.00 | Tolerated | 0.1506 | 0.2189 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1936C>A | L646M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta’s stability analysis remains uncertain. Overall, the evidence overwhelmingly supports a benign classification for this variant, 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 | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -1.911 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.70 | Ambiguous | 0.1 | 1.66 | Ambiguous | 1.18 | Ambiguous | -1.10 | Stabilizing | 0.106 | Likely Benign | 1.86 | Neutral | 0.211 | Benign | 0.055 | Benign | 3.57 | Benign | 1.00 | Tolerated | 0.2041 | 0.3427 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| 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.1993T>G | Y665D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y665D is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Uncertain. No evidence from these tools contradicts the ClinVar status, which is currently unreported. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with a pathogenic consensus from SGM‑Consensus—suggests the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.086641 | Uncertain | 0.922 | 0.361 | 0.000 | -10.101 | Likely Pathogenic | 0.737 | Likely Pathogenic | Likely Benign | 1.15 | Ambiguous | 0.2 | 1.30 | Ambiguous | 1.23 | Ambiguous | 0.15 | Likely Benign | 0.227 | Likely Benign | -3.67 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.75 | Benign | 1.00 | Tolerated | 0.3838 | 0.0573 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.2020A>T | T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.320 | Likely Benign | 0.082 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.11 | Likely Benign | -0.14 | Likely Benign | 0.084 | Likely Benign | 0.47 | Neutral | 0.107 | Benign | 0.033 | Benign | 3.47 | Benign | 1.00 | Tolerated | 0.3329 | 0.4938 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2021C>G | T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.320 | Likely Benign | 0.082 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.11 | Likely Benign | -0.14 | Likely Benign | 0.088 | Likely Benign | 0.47 | Neutral | 0.107 | Benign | 0.033 | Benign | 3.47 | Benign | 1.00 | Tolerated | 0.3329 | 0.4938 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2027G>C | S676T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (Uncertain) and Foldetta (Uncertain). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -5.621 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 0.34 | Likely Benign | 0.57 | Ambiguous | -0.36 | Likely Benign | 0.098 | Likely Benign | 0.91 | Neutral | 0.050 | Benign | 0.017 | Benign | 3.52 | Benign | 1.00 | Tolerated | 0.1575 | 0.6286 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2032A>G | S678G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, REVEL, FoldX, premPS, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is listed as “Uncertain.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -4.379 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.40 | Likely Benign | -0.24 | Likely Benign | 0.082 | Likely Benign | 1.90 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.43 | Benign | 1.00 | Tolerated | 0.2807 | 0.4961 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.2080G>T | A694S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The only inconclusive results come from Rosetta and premPS, which are listed as uncertain and do not influence the overall assessment. High‑accuracy predictors reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Consequently, the variant is most likely benign, and this prediction is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -0.326 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.41 | Likely Benign | -0.53 | Ambiguous | 0.092 | Likely Benign | 0.70 | Neutral | 0.013 | Benign | 0.021 | Benign | 3.57 | Benign | 1.00 | Tolerated | 0.2725 | 0.4231 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.2101C>T | P701S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701S (ClinVar ID 2995856.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33441360‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). No tool in the dataset predicts a pathogenic outcome; all remaining predictions are either benign or uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Based on the collective evidence, the variant is most likely benign, 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 | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | Uncertain | 1 | 6-33441360-C-T | 3 | 1.86e-6 | -4.375 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 1.33 | Ambiguous | 0.0 | 0.12 | Likely Benign | 0.73 | Ambiguous | -0.36 | Likely Benign | 0.132 | Likely Benign | 0.78 | Neutral | 0.044 | Benign | 0.025 | Benign | 3.48 | Benign | 1.00 | Tolerated | 3.47 | 10 | 0.3149 | 0.3782 | -1 | 1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||
| 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.2149C>A | L717I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only two tools—polyPhen‑2 HumDiv and HumVar—predict a pathogenic outcome, while premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -4.836 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.30 | Likely Benign | -0.73 | Ambiguous | 0.182 | Likely Benign | 0.60 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.43 | Benign | 1.00 | Tolerated | 0.0712 | 0.2570 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.2165G>C | S722T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722T is reported in gnomAD (6‑33441630‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while FoldX is uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441630-G-C | 1 | 6.20e-7 | -5.734 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | -0.32 | Likely Benign | 0.11 | Likely Benign | -0.12 | Likely Benign | 0.118 | Likely Benign | -0.57 | Neutral | 0.921 | Possibly Damaging | 0.414 | Benign | 2.57 | Benign | 1.00 | Tolerated | 3.50 | 8 | 0.1357 | 0.4363 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||
| c.2177G>C | R726T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the aggregate 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 | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -5.249 | Likely Benign | 0.661 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.0 | -0.11 | Likely Benign | 0.36 | Likely Benign | -0.01 | Likely Benign | 0.200 | Likely Benign | -0.90 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.74 | Benign | 1.00 | Tolerated | 0.1685 | 0.4569 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||
| c.2186A>C | N729T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729T is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID 6‑33441651‑A‑C). Consensus among the majority of in‑silico predictors is benign: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, the evidence strongly supports a benign effect, and this conclusion does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | 6-33441651-A-C | 1 | 6.20e-7 | -1.952 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.3 | 1.73 | Ambiguous | 1.13 | Ambiguous | -0.34 | Likely Benign | 0.052 | Likely Benign | -0.52 | Neutral | 0.123 | Benign | 0.042 | Benign | 3.33 | Benign | 1.00 | Tolerated | 3.59 | 7 | 0.1201 | 0.4805 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.2198A>T | Q733L 2D  AIThe SynGAP1 missense variant Q733L 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. 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. No Foldetta stability analysis is available, so it does not influence the assessment. 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 | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -3.465 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -2.04 | Neutral | 0.905 | Possibly Damaging | 0.408 | Benign | 2.55 | Benign | 1.00 | Tolerated | 0.0736 | 0.4291 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2201C>T | P734L 2D AIThe SynGAP1 missense variant P734L is reported in gnomAD (variant ID 6‑33441666‑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 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 is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence indicates 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | 6-33441666-C-T | 3 | 1.86e-6 | -3.472 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -2.11 | Neutral | 0.897 | Possibly Damaging | 0.330 | Benign | 2.69 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.2390 | 0.5059 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2210A>T | Q737L 2D AIThe SynGAP1 missense variant Q737L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -2.789 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.44 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.80 | Benign | 1.00 | Tolerated | 0.0958 | 0.5494 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2251C>A | P751T 2D AIThe SynGAP1 missense variant P751T is not reported 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. Taken together, 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -5.111 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.65 | Neutral | 0.679 | Possibly Damaging | 0.348 | Benign | 2.71 | Benign | 1.00 | Tolerated | 0.1613 | 0.5704 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2273A>T | Y758F 2D AIThe SynGAP1 missense variant Y758F is not reported 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 | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -1.431 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.79 | Neutral | 0.679 | Possibly Damaging | 0.371 | Benign | 2.75 | Benign | 1.00 | Tolerated | 0.2441 | 0.2835 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2275A>C | M759L 2D AIThe SynGAP1 missense variant M759L is listed in ClinVar with an uncertain significance (ClinVar ID 942432.0) and is present in gnomAD (gnomAD ID 6‑33441740‑A‑C). 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 classifications. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, 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, 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | 6-33441740-A-C | 2 | 1.24e-6 | -2.431 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.53 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.84 | Benign | 1.00 | Tolerated | 3.99 | 5 | 0.1308 | 0.4005 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2275A>T | M759L 2D AIThe SynGAP1 missense variant M759L 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, derived from a 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -2.431 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.53 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.84 | Benign | 1.00 | Tolerated | 3.99 | 5 | 0.1308 | 0.4005 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2299A>G | I767V 2D AIThe SynGAP1 missense variant I767V is listed in ClinVar (ID 1402700.0) with an “Uncertain” clinical significance and is not reported in 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 all return benign scores. The SGM‑Consensus, which aggregates the 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, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability predictions) has no available result for this variant. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the current ClinVar status of uncertainty. 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 | -2.791 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.096 | Likely Benign | 0.10 | Neutral | 0.072 | Benign | 0.029 | Benign | 4.21 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1418 | 0.4227 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2314T>C | F772L 2D AIThe SynGAP1 missense variant F772L is listed in gnomAD (6‑33442472‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442472-T-C | 1 | 1.28e-6 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.161 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.2316C>A | F772L 2D AIThe SynGAP1 missense variant F772L is catalogued in gnomAD (ID 6‑33442474‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence indicates that F772L is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442474-C-A | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.2316C>G | F772L 2D AIThe SynGAP1 missense variant F772L has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability data are available, so it is treated as unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.2321C>T | A774V 2D AIThe SynGAP1 missense variant A774V is catalogued in gnomAD (ID 6‑33442479‑C‑T) 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 scores the variant as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. 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) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | 6-33442479-C-T | 1 | 1.28e-6 | -3.075 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.73 | Neutral | 0.000 | Benign | 0.003 | Benign | 4.20 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1070 | 0.6659 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| 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.2347A>C | M783L 2D AIThe SynGAP1 missense variant M783L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -1.915 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -0.48 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.1727 | 0.4461 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2347A>T | M783L 2D AIThe SynGAP1 missense variant M783L 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 change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability approach, has no available result for this variant. Overall, the collective evidence strongly supports a benign interpretation, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction. 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 | -1.915 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.48 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.1727 | 0.4461 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2350G>A | A784T 2D AIThe SynGAP1 missense variant A784T is listed in ClinVar (ID 962668.0) as Benign and is not reported in gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. A Foldetta stability analysis is unavailable, so it does not influence the overall interpretation. Based on the unanimous benign predictions and the ClinVar designation, the variant is most likely benign, with no contradiction to the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | Benign | 1 | -3.579 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 1.23 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1493 | 0.6659 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.2399G>C | G800A 2D AIThe SynGAP1 missense variant G800A is listed in gnomAD (6-33442951‑G‑C) but has no ClinVar entry. Across the available in‑silico predictors, every tool reports a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Based on the unanimous benign predictions and the absence of any pathogenic calls, 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 | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | 6-33442951-G-C | 7 | 4.34e-6 | -3.550 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.48 | Neutral | 0.011 | Benign | 0.006 | Benign | 2.78 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.3466 | 0.4850 | 0 | 1 | 2.2 | 14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||
| c.2461T>A | C821S 2D AIThe SynGAP1 missense variant C821S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for C821S, 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 | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -0.425 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.91 | Benign | 1.00 | Tolerated | 0.5284 | 0.2012 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||
| c.2462G>C | C821S 2D AIThe SynGAP1 missense variant C821S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for C821S, 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 | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -0.425 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.314 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.91 | Benign | 1.00 | Tolerated | 0.5284 | 0.2012 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||
| 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.2495A>T | Q832L 2D AIThe SynGAP1 missense variant Q832L is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, 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 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 | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -2.299 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.58 | Neutral | 0.811 | Possibly Damaging | 0.424 | Benign | 2.84 | Benign | 1.00 | Tolerated | 0.0676 | 0.4852 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>C | V837A 2D AIThe SynGAP1 missense variant V837A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, 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. 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 | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -1.400 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.073 | Likely Benign | -0.41 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 1.00 | Tolerated | 0.3058 | 0.2106 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| 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.2555G>C | G852A 2D AIThe SynGAP1 missense variant G852A is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -4.493 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -0.35 | Neutral | 0.393 | Benign | 0.321 | Benign | 4.25 | Benign | 1.00 | Tolerated | 0.3895 | 0.4934 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2570G>A | S857N 2D AIThe SynGAP1 missense variant S857N 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 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 | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -5.065 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.24 | Neutral | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 4.09 | Benign | 1.00 | Tolerated | 0.1515 | 0.5034 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2639C>T | A880V 2D AIThe SynGAP1 missense variant A880V is reported in gnomAD (variant ID 6‑33443191‑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 the change 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for A880V, 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 | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | 6-33443191-C-T | 1 | 6.20e-7 | -5.440 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.11 | Neutral | 0.761 | Possibly Damaging | 0.399 | Benign | 2.58 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0947 | 0.5362 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2660C>G | P887R 2D AIThe SynGAP1 missense variant P887R 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. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for P887R, 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 | 0.716283 | Disordered | 0.602269 | Binding | 0.348 | 0.925 | 0.500 | -4.759 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.06 | Neutral | 0.802 | Possibly Damaging | 0.413 | Benign | 2.76 | Benign | 1.00 | Tolerated | 0.1306 | 0.2238 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2678A>T | Q893L 2D AIThe SynGAP1 missense variant Q893L 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 benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -1.964 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.92 | Neutral | 0.451 | Benign | 0.209 | Benign | 2.82 | Benign | 1.00 | Tolerated | 0.0904 | 0.5643 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2711T>A | M904K 2D  AIThe SynGAP1 missense variant M904K is not reported 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available 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 | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -2.333 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.033 | Likely Benign | -1.08 | Neutral | 0.277 | Benign | 0.137 | Benign | 2.80 | Benign | 1.00 | Tolerated | 0.1696 | 0.0871 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| 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.2726T>C | M909T 2D AIThe SynGAP1 missense variant M909T 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for M909T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.053 | Likely Benign | 0.647 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.74 | Neutral | 0.901 | Possibly Damaging | 0.430 | Benign | 2.86 | Benign | 1.00 | Tolerated | 0.2157 | 0.2085 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2742C>A | D914E 2D AIThe SynGAP1 missense variant D914E is reported in gnomAD (ID 6‑33443294‑C‑A) 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | 6-33443294-C-A | 5 | 3.10e-6 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2742C>G | D914E 2D AIThe SynGAP1 missense variant D914E 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. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for D914E, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2747T>C | V916A 2D AIThe SynGAP1 missense variant V916A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates a pathogenic effect, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and the Foldetta stability analysis is not available. Based on the collective predictions, 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.524 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.18 | Neutral | 0.244 | Benign | 0.171 | Benign | 2.91 | Benign | 1.00 | Tolerated | 0.3455 | 0.2841 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2765G>T | R922L 2D AIThe SynGAP1 missense variant R922L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign interpretation. Therefore, the variant is most likely benign according to the consensus of predictive tools, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -3.714 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 0.150 | Likely Benign | 0.84 | Neutral | 0.983 | Probably Damaging | 0.828 | Possibly Damaging | 3.04 | Benign | 1.00 | Tolerated | 0.2033 | 0.5022 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2767A>G | I923V 2D AIThe SynGAP1 missense variant I923V is reported in gnomAD (ID 6‑33443319‑A‑G) and has no ClinVar entry. 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. 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, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Therefore, the variant is most likely benign, with no conflict with ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.964857 | Binding | 0.292 | 0.852 | 0.250 | 6-33443319-A-G | 1 | 6.20e-7 | -2.010 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.05 | Neutral | 0.028 | Benign | 0.009 | Benign | 2.76 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1589 | 0.4060 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2834A>T | H945L 2D AIThe SynGAP1 missense variant H945L is reported in gnomAD (ID 6‑33443386‑A‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | 6-33443386-A-T | 2 | 1.24e-6 | -4.741 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.16 | Neutral | 0.948 | Possibly Damaging | 0.863 | Possibly Damaging | 5.05 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.2085 | 0.4526 | -3 | -2 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||
| c.2842G>A | G948S 2D AIThe SynGAP1 missense variant G948S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this benign assessment: 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 predictor, has no available result for this variant. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -4.760 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.177 | Likely Benign | 1.09 | Neutral | 0.068 | Benign | 0.026 | Benign | 4.57 | Benign | 1.00 | Tolerated | 0.2466 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>T | P954S 2D AIThe SynGAP1 missense variant P954S is listed in ClinVar as Benign (ClinVar ID 833606.0) and is present in gnomAD (ID 6‑33443412‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | Likely Benign | 1 | 6-33443412-C-T | 1 | 6.20e-7 | -3.525 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.25 | Neutral | 0.954 | Possibly Damaging | 0.812 | Possibly Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3088 | 0.5619 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2872C>A | H958N 2D AIThe SynGAP1 missense variant H958N is not reported 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, 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 | 0.985964 | Disordered | 0.976011 | Binding | 0.371 | 0.913 | 0.750 | -8.644 | Likely Pathogenic | 0.097 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.56 | Neutral | 0.836 | Possibly Damaging | 0.232 | Benign | 4.17 | Benign | 1.00 | Tolerated | 0.2358 | 0.3638 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2894A>T | H965L 2D AIThe SynGAP1 missense variant H965L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect. Benign predictors include REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool in the dataset returned a pathogenic prediction. Consensus predictors such as SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classify the variant as Likely Benign. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus is 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 exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.978700 | Binding | 0.342 | 0.882 | 0.750 | -6.708 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -1.66 | Neutral | 0.033 | Benign | 0.018 | Benign | 4.06 | Benign | 1.00 | Tolerated | 0.1606 | 0.5338 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2968T>A | S990T 2D AIThe SynGAP1 missense variant S990T 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, derived from a 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 | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.439 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.06 | Neutral | 0.001 | Benign | 0.007 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1524 | 0.5598 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3004C>A | H1002N 2D AIThe SynGAP1 missense variant H1002N 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 SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data to contradict. Overall, the preponderance of evidence points to a benign effect for H1002N, 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -5.622 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -1.41 | Neutral | 0.801 | Possibly Damaging | 0.596 | Possibly Damaging | 2.76 | Benign | 1.00 | Tolerated | 0.2084 | 0.3057 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3024T>A | D1008E 2D AIThe SynGAP1 D1008E missense variant is catalogued in gnomAD (6‑33443576‑T‑A) 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). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, providing no definitive signal. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also reports it as likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443576-T-A | 1 | 6.20e-7 | -2.809 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2315 | 0.6303 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.3024T>G | D1008E 2D AIThe SynGAP1 missense variant D1008E is listed in gnomAD (ID 6‑33443576‑T‑G) 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 is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta provides no data. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443576-T-G | -2.809 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2315 | 0.6303 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| 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.3085C>A | Q1029K 2D AIThe SynGAP1 missense variant Q1029K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta data is missing. Overall, the majority of evidence points to a benign impact for Q1029K, 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.698 | Likely Benign | 0.516 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -1.18 | Neutral | 0.771 | Possibly Damaging | 0.482 | Possibly Damaging | 2.79 | Benign | 1.00 | Tolerated | 0.1656 | 0.4196 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3092T>C | M1031T 2D AIThe SynGAP1 missense variant M1031T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443644‑T‑C). In silico prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is AlphaMissense‑Default, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are not available. **Thus, 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. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | Uncertain | 1 | 6-33443644-T-C | 2 | 1.24e-6 | -1.863 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.085 | Likely Benign | -0.24 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.67 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1587 | 0.2264 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||
| c.3097T>G | S1033A 2D AIThe SynGAP1 missense variant S1033A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions indicates that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.107 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.06 | Neutral | 0.220 | Benign | 0.085 | Benign | 2.81 | Benign | 1.00 | Tolerated | 0.4387 | 0.5282 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3122C>T | P1041L 2D AIThe SynGAP1 missense variant P1041L 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign. 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 ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.901 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -3.14 | Deleterious | 0.905 | Possibly Damaging | 0.375 | Benign | 5.46 | Benign | 1.00 | Tolerated | 0.2357 | 0.6664 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| 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.3134C>T | A1045V 2D AIThe SynGAP1 missense variant A1045V 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -4.229 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.35 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.06 | Benign | 1.00 | Tolerated | 0.1487 | 0.5474 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3149G>C | G1050A 2D AIThe SynGAP1 missense variant G1050A 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 | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -5.514 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 0.18 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.68 | Benign | 1.00 | Tolerated | 0.3349 | 0.5133 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3152G>C | G1051A 2D AIThe SynGAP1 missense variant G1051A is not 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), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM 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 (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign effect, 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 | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -6.406 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.406 | Likely Benign | -0.14 | Neutral | 0.009 | Benign | 0.004 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 0.3353 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3155G>C | G1052A 2D AIThe SynGAP1 missense variant G1052A 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 supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -6.945 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.382 | Likely Benign | -0.14 | Neutral | 0.649 | Possibly Damaging | 0.287 | Benign | 3.93 | Benign | 1.00 | Tolerated | 0.3259 | 0.4949 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3161G>C | G1054A 2D AIThe SynGAP1 missense variant G1054A is catalogued in gnomAD (ID 6‑33443713‑G‑C) but has no ClinVar entry. Across a broad panel of in‑silico predictors, every tool reports a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Based on the unanimous benign predictions and the lack of any ClinVar pathogenic classification, 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 | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | 6-33443713-G-C | -6.786 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -0.05 | Neutral | 0.288 | Benign | 0.071 | Benign | 4.03 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3305 | 0.5144 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3164G>C | G1055A 2D AIThe SynGAP1 missense variant G1055A 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 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 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 | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -6.835 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.15 | Neutral | 0.649 | Possibly Damaging | 0.148 | Benign | 3.30 | Benign | 1.00 | Tolerated | 0.3350 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3206A>C | Q1069P 2D AIThe SynGAP1 missense variant Q1069P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -3.458 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.211 | Likely Benign | 0.75 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 2.73 | Benign | 1.00 | Tolerated | 0.2179 | 0.5944 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.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.3223C>A | Q1075K 2D AIThe SynGAP1 missense variant Q1075K (ClinVar ID 2762879.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” because three of the four contributing tools predict benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to 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 | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | Uncertain | 1 | -5.135 | Likely Benign | 0.728 | Likely Pathogenic | Likely Benign | 0.134 | Likely Benign | -0.67 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 2.75 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1898 | 0.4411 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.323A>G | K108R 2D AIThe SynGAP1 missense variant K108R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432188‑A‑G). 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, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is benign; 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 | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | Uncertain | 1 | 6-33432188-A-G | 6 | 3.72e-6 | -2.892 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.184 | Likely Benign | 0.37 | Neutral | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 4.22 | Benign | 1.00 | Tolerated | 3.61 | 5 | 0.5286 | 0.1229 | Weaken | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||
| c.3245A>T | Q1082L 2D AIThe SynGAP1 missense variant Q1082L 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -3.284 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.30 | Neutral | 0.224 | Benign | 0.058 | Benign | 4.12 | Benign | 1.00 | Tolerated | 0.0979 | 0.6824 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3280T>G | S1094A 2D AIThe SynGAP1 missense variant S1094A 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, so the pathogenic‑prediction group is empty. 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 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 lack of ClinVar evidence. 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 | -3.595 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -0.78 | Neutral | 0.447 | Benign | 0.252 | Benign | 2.66 | Benign | 1.00 | Tolerated | 0.4692 | 0.5403 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3283C>T | P1095S 2D AIThe SynGAP1 missense variant P1095S is reported in gnomAD (ID 6‑33443835‑C‑T) 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 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, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | 6-33443835-C-T | 7 | 4.51e-6 | -3.819 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.64 | Neutral | 0.207 | Benign | 0.072 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3150 | 0.5963 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3311C>T | P1104L 2D AIThe SynGAP1 missense variant P1104L 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 (majority vote) also predicts Likely Benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, points to a benign impact. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.846 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.33 | Neutral | 0.626 | Possibly Damaging | 0.168 | Benign | 2.81 | Benign | 1.00 | Tolerated | 0.2264 | 0.6795 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3343A>C | I1115L 2D AIThe SynGAP1 missense variant I1115L is listed in ClinVar (ID 4178654) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443895‑A‑C). 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 reports a pathogenic effect, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this benign consensus: 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, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | Uncertain | 1 | 6-33443895-A-C | 1 | 7.56e-7 | -2.308 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.46 | Neutral | 0.004 | Benign | 0.007 | Benign | 2.82 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.1154 | 0.4575 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||
| c.3356G>C | G1119A 2D AIThe SynGAP1 missense variant G1119A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. 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 | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -6.703 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 3.93 | Benign | 1.00 | Tolerated | 0.3591 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3368G>C | G1123A 2D AIThe SynGAP1 missense variant G1123A 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated methods. High‑accuracy tools 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 | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -6.720 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -0.55 | Neutral | 0.264 | Benign | 0.103 | Benign | 4.38 | Benign | 1.00 | Tolerated | 0.3544 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3380G>C | G1127A 2D AIThe SynGAP1 missense variant G1127A is listed in ClinVar (ID 426748.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443932‑G‑C). Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods 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 predictor combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the evidence strongly supports a benign classification, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Conflicting | 4 | 6-33443932-G-C | 4 | 2.68e-6 | -5.949 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.83 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.3420 | 0.4933 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3383G>A | G1128E 2D  AIThe SynGAP1 missense variant G1128E is present in gnomAD (6‑33443935‑G‑A) and has no ClinVar entry. In silico predictors that agree on a benign effect include REVEL, PROVEAN, PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is a high‑accuracy majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its stability impact remains unknown. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | 6-33443935-G-A | 1 | 6.70e-7 | -5.580 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.235 | Likely Benign | -0.24 | Neutral | 0.002 | Benign | 0.008 | Benign | 4.43 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.1610 | 0.4497 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3418A>G | T1140A 2D AIThe SynGAP1 missense variant T1140A 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 | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -3.838 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.36 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.71 | Benign | 1.00 | Tolerated | 0.3949 | 0.3463 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3464T>C | V1155A 2D AIThe SynGAP1 missense variant V1155A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default 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 show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.019 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.224 | Likely Benign | 0.77 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 3.15 | Benign | 1.00 | Tolerated | 0.3070 | 0.1859 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| 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.3559A>C | M1187L 2D AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3559A>T | M1187L 2D AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign effect for M1187L, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.359G>C | G120A 2D AIThe SynGAP1 missense variant G120A 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 | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -3.477 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.37 | Benign | 1.00 | Tolerated | 0.4003 | 0.4565 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3610T>G | S1204A 2D AIThe SynGAP1 missense variant S1204A is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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 predict a neutral 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. 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 | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | -5.134 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -0.53 | Neutral | 0.061 | Benign | 0.047 | Benign | 5.45 | Benign | 1.00 | Tolerated | 0.4943 | 0.3167 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3629A>G | H1210R 2D AIThe SynGAP1 missense variant H1210R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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 predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments corroborate this benign consensus: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields “Likely Benign.” Foldetta results are not available, so they do not influence the interpretation. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | 0.860 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.89 | Neutral | 0.178 | Benign | 0.089 | Benign | 3.25 | Benign | 1.00 | Tolerated | 0.1535 | 0.2384 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||
| c.3633G>A | M1211I 2D AIThe SynGAP1 missense variant M1211I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33446625-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are AlphaMissense‑Default, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore point to a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar “Uncertain” status. 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 | Uncertain | 1 | 6-33446625-G-A | 3 | 1.86e-6 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1214 | 0.2839 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||
| c.3633G>C | M1211I 2D AIThe SynGAP1 missense variant M1211I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1214 | 0.2839 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.3633G>T | M1211I 2D AIThe SynGAP1 missense variant M1211I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default 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 (three benign votes versus one pathogenic). High‑accuracy assessment by AlphaMissense‑Optimized confirms a benign prediction, whereas the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for M1211I, 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 | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1214 | 0.2839 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.3638A>C | N1213T 2D AIThe SynGAP1 missense variant N1213T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446630‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0968 | 0.4546 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||
| c.364C>G | P122A 2D AIThe SynGAP1 missense variant P122A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.105 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.66 | Neutral | 0.363 | Benign | 0.096 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.3991 | 0.4286 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3673T>G | S1225A 2D AIThe SynGAP1 missense variant S1225A is not reported in ClinVar and is absent from gnomAD, indicating no known clinical annotation or 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. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -3.157 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.257 | Likely Benign | -0.16 | Neutral | 0.139 | Benign | 0.089 | Benign | 5.51 | Benign | 1.00 | Tolerated | 0.3804 | 0.3823 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3697A>C | I1233L 2D AIThe SynGAP1 missense variant I1233L 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, and FATHMM all score the substitution as benign, and AlphaMissense‑Optimized also predicts a benign outcome. No tool predicts pathogenicity; 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 corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates likely benign; Foldetta data are not available. Overall, the consensus of available predictions points to a benign effect, and this is consistent with the lack of ClinVar evidence or gnomAD observation. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -3.031 | Likely Benign | 0.382 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -0.01 | Neutral | 0.211 | Benign | 0.108 | Benign | 2.95 | Benign | 1.00 | Tolerated | 0.0631 | 0.3246 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3703A>C | M1235L 2D AIThe SynGAP1 missense variant M1235L is reported as “Likely Benign” by the SGM‑Consensus method and has no ClinVar entry, indicating it has not been classified in that database. It is also absent from gnomAD, so its allele frequency is not documented there. Across the spectrum of in‑silico predictors, all tools that provide a verdict—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—concur that the substitution is benign; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Based on the unanimous benign predictions and the lack of ClinVar classification, the variant is most likely benign, with no contradiction to existing clinical data. 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 | -2.013 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1363 | 0.3935 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3703A>T | M1235L 2D AIThe SynGAP1 missense variant M1235L is reported as “Likely Benign” in the SGM‑Consensus and has no ClinVar entry, and it is not listed 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 reinforce this view: 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. Based on the unanimous benign predictions and lack of ClinVar or gnomAD evidence, 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 | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -2.013 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1363 | 0.3935 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3706C>G | Q1236E 2D AIThe SynGAP1 missense variant Q1236E 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 unavailable. Overall, the preponderance of evidence supports a benign classification for Q1236E, 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 | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -0.371 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.263 | Likely Benign | 0.66 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 3.18 | Benign | 1.00 | Tolerated | 0.0985 | 0.1130 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3727C>G | Q1243E 2D AIThe SynGAP1 missense variant Q1243E 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 the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -1.439 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.88 | Neutral | 0.166 | Benign | 0.146 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.1067 | 0.0930 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| 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.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.3758C>T | A1253V 2D AIThe SynGAP1 missense variant A1253V is predicted to be benign by every evaluated in‑silico tool. Benign predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized classifies the variant as 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, was not available for this variant. ClinVar contains no entry for A1253V, and the variant is absent from gnomAD. Based on the unanimous benign predictions and lack of conflicting evidence, 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 | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -4.706 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.20 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.85 | Benign | 1.00 | Tolerated | 0.0784 | 0.4473 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| c.3777C>G | I1259M 2D AIThe SynGAP1 missense variant I1259M is catalogued in gnomAD (ID 6‑33446769‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score, whereas PolyPhen‑2 (HumDiv and HumVar) classify the change as pathogenic. The high‑accuracy AlphaMissense‑Optimized tool reports a benign effect, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, a protein‑folding stability method that integrates 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 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 | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | 6-33446769-C-G | 2 | 1.24e-6 | -5.177 | Likely Benign | 0.447 | Ambiguous | Likely Benign | 0.227 | Likely Benign | 1.35 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0576 | 0.2358 | 1 | 2 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||
| c.3790G>A | G1264S 2D AIThe SynGAP1 missense variant G1264S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: benign predictions are made by 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 classifies the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -0.797 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.82 | Neutral | 0.062 | Benign | 0.033 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.2376 | 0.4256 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3832C>G | P1278A 2D AIThe SynGAP1 missense variant P1278A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 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 | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.187 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.3597 | 0.3353 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3847C>G | P1283A 2D AIThe SynGAP1 missense variant P1283A 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, so they do not influence the overall assessment. Consequently, the variant is most likely benign based on the collective predictions, 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 | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | -3.656 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 1.42 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.2874 | 0.3370 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3850C>G | L1284V 2D AIThe SynGAP1 missense variant L1284V 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 | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.329 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.90 | Neutral | 0.008 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 0.1419 | 0.1883 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3854C>T | P1285L 2D AIThe SynGAP1 missense variant P1285L 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 classification for P1285L, 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 | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | -3.663 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.06 | Neutral | 0.072 | Benign | 0.029 | Benign | 4.31 | Benign | 1.00 | Tolerated | 0.2159 | 0.4539 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3858A>C | E1286D 2D AIThe SynGAP1 missense variant E1286D is not reported in ClinVar and is absent from gnomAD. All available 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 predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.3858A>T | E1286D 2D AIThe SynGAP1 missense variant E1286D is listed in ClinVar (ID 469159.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33447906‑A‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool in the set predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, 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 computational evidence strongly supports 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 | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | Conflicting | 4 | 6-33447906-A-T | 143 | 9.22e-5 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3865A>C | K1289Q 2D AIThe SynGAP1 missense variant K1289Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -2.940 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.55 | Neutral | 0.004 | Benign | 0.004 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.4002 | 0.0590 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>A | R1290K 2D AIThe SynGAP1 missense variant R1290K 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 suggest that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -3.749 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.52 | Neutral | 0.004 | Benign | 0.006 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.3342 | 0.3113 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3874C>A | L1292I 2D AIThe SynGAP1 missense variant L1292I 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 | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -5.480 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.71 | Neutral | 0.002 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 0.1101 | 0.3323 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3890G>A | R1297K 2D AIThe SynGAP1 missense variant R1297K is catalogued in gnomAD (ID 6‑33451764‑G‑A) 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 tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting a pathogenic outcome. 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 classification. Foldetta stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign interpretation, and this assessment does not conflict with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451764-G-A | 1 | 6.20e-7 | -3.780 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4109 | 0.2801 | 2 | 3 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||
| c.3893A>G | Q1298R 2D AIThe SynGAP1 missense variant Q1298R 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -2.643 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.1142 | 0.1628 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>A | L1299I 2D AIThe SynGAP1 missense variant L1299I 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 results are unavailable. Based on the collective 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 | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.264 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.396 | Likely Benign | 0.71 | Neutral | 0.003 | Benign | 0.004 | Benign | 3.20 | Benign | 1.00 | Tolerated | 0.1014 | 0.3893 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3898C>G | P1300A 2D AIThe SynGAP1 missense variant P1300A is reported in gnomAD (ID 6‑33451772‑C‑G) 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 predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-G | 2 | 1.24e-6 | -3.802 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.55 | Neutral | 0.008 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3342 | 0.3744 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| 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.3910C>G | P1304A 2D AIThe SynGAP1 missense variant P1304A 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, derived from a 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.072 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.35 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.2923 | 0.4117 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3913A>G | T1305A 2D AIThe SynGAP1 missense variant T1305A is listed in ClinVar (ID 411587.0) with an “Uncertain” clinical significance and is present in the gnomAD database (variant ID 6‑33451787‑A‑G). 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 reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, 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 | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | Conflicting | 4 | 6-33451787-A-G | 30 | 1.86e-5 | -2.692 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.74 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.24 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4533 | 0.4746 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||
| c.3919C>G | P1307A 2D AIThe SynGAP1 missense variant P1307A is catalogued in gnomAD (ID 6‑33451793‑C‑G) 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 tolerated or benign. No tool in the dataset 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) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Based on the consensus of all predictions, the variant is most likely benign, and this does not contradict ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | 6-33451793-C-G | 1 | 6.20e-7 | -4.042 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.49 | Neutral | 0.003 | Benign | 0.006 | Benign | 3.11 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3747 | 0.4451 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3925G>C | V1309L 2D AIThe SynGAP1 missense variant V1309L 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, derived from a 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 trend: 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 | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.543 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 1.41 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.0944 | 0.4212 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3925G>T | V1309L 2D AIThe SynGAP1 missense variant V1309L 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available 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 | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.543 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 1.41 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.0944 | 0.4212 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>T | P1313L 2D AIThe SynGAP1 missense variant P1313L 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 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.588 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 1.90 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0.2489 | 0.6948 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3955G>T | A1319S 2D AIThe SynGAP1 missense variant A1319S is catalogued in gnomAD (ID 6‑33451829‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. Grouping by consensus, all listed predictors fall into the benign category, with no pathogenic predictions to counterbalance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, 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 | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-T | -4.557 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.094 | Likely Benign | 0.79 | Neutral | 0.174 | Benign | 0.112 | Benign | 4.17 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2957 | 0.5676 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3961C>A | P1321T 2D AIThe SynGAP1 missense variant P1321T is catalogued in gnomAD (ID 6‑33451835‑C‑A) 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 variant 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, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion 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 | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-A | -4.946 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 1.07 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.25 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2016 | 0.5901 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3979C>A | P1327T 2D AIThe SynGAP1 missense variant P1327T is reported in gnomAD (ID 6‑33451853‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. Taken together, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-A | -5.263 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.20 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.51 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1386 | 0.4779 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.4018A>T | T1340S 2D AIThe SynGAP1 missense variant T1340S 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the available 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 | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -2.698 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.87 | Benign | 1.00 | Tolerated | 0.3436 | 0.4521 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4019C>G | T1340S 2D AIThe SynGAP1 missense variant T1340S 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the available 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 | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -2.698 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.083 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.87 | Benign | 1.00 | Tolerated | 0.3436 | 0.4521 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4021G>T | A1341S 2D AIThe SynGAP1 missense variant A1341S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33451895-G-T). All available 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) is “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | Uncertain | 1 | 6-33451895-G-T | -2.867 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.80 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2784 | 0.5884 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.415A>G | S139G 2D AIThe SynGAP1 missense variant S139G 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. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, and AlphaMissense‑Optimized confirms a benign prediction. Foldetta, a protein‑folding stability method, 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | 1.647 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 1.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.29 | Benign | 1.00 | Tolerated | 0.2712 | 0.3414 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.524A>C | Q175P 2D AIThe SynGAP1 missense variant Q175P is reported in gnomAD (ID 6‑33435166‑A‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the substitution as benign. The consensus from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy predictors corroborate this assessment: AlphaMissense‑Optimized predicts a benign outcome, and the SGM‑Consensus (majority vote) confirms a likely benign status. No high‑accuracy folding‑stability analysis (Foldetta) is available for this residue, so stability effects remain unassessed. Overall, the collective evidence points to a benign impact for Q175P, and this conclusion is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | 6-33435166-A-C | 1 | 6.20e-7 | -6.995 | Likely Benign | 0.432 | Ambiguous | Likely Benign | 0.211 | Likely Benign | 1.55 | Neutral | 0.396 | Benign | 0.188 | Benign | 4.20 | Benign | 1.00 | Tolerated | 3.61 | 5 | 0.2075 | 0.4584 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||
| c.529T>C | F177L 2D AIThe SynGAP1 missense variant F177L is not reported 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, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports 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. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.184 | Likely Benign | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 0.2376 | 0.4280 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.531T>A | F177L 2D AIThe SynGAP1 missense variant F177L is not reported 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, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports 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. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 0.2376 | 0.4280 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.531T>G | F177L 2D AIThe SynGAP1 missense variant F177L is not reported 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, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports 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. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 0.2376 | 0.4280 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.542A>G | H181R 2D AIThe SynGAP1 missense variant H181R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, 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 likewise indicates 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -3.668 | Likely Benign | 0.521 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -0.11 | Neutral | 0.818 | Possibly Damaging | 0.188 | Benign | 4.35 | Benign | 1.00 | Tolerated | 0.1585 | 0.1782 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.578C>T | A193V 2D AIThe SynGAP1 A193V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is 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 | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -3.548 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | 0.52 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0.1169 | 0.6775 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.591G>C | E197D 2D AIThe SynGAP1 missense variant E197D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions 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 | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | 0.784 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.81 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.66 | Benign | 1.00 | Tolerated | 0.1579 | 0.3345 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.591G>T | E197D 2D AIThe SynGAP1 missense variant E197D 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 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 | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | 0.784 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.81 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.66 | Benign | 1.00 | Tolerated | 0.1579 | 0.3345 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.603T>A | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (ClinVar ID 3004688.0) is classified as **Benign** in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as **Benign**, the SGM‑Consensus as **Likely Benign**, and Foldetta as **Uncertain**. Taken together, the overwhelming majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation. Thus, the variant is most likely benign, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | Benign | 1 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | 0.165 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 0.1069 | 0.5505 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||||
| c.603T>G | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (gnomAD ID 6‑33435245‑T‑G) is listed in ClinVar with an uncertain significance. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign. Only polyPhen‑2 HumDiv predicts pathogenicity, while Rosetta, Foldetta, and AlphaMissense‑Default remain inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “likely benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta is inconclusive. Taken together, the preponderance of evidence points to a benign impact, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | Conflicting | 2 | 6-33435245-T-G | 20 | 1.24e-5 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | 0.165 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 0.1069 | 0.5505 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.610T>A | S204T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204T 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic effect. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors classify S204T as benign, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -4.164 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.97 | Ambiguous | -0.52 | Ambiguous | 0.104 | Likely Benign | 0.55 | Neutral | 0.462 | Possibly Damaging | 0.173 | Benign | 4.19 | Benign | 1.00 | Tolerated | 0.0857 | 0.5063 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.682A>T | T228S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. Taken together, the overwhelming majority of evidence indicates a benign impact for T228S. 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 | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -2.028 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.48 | Likely Benign | 0.05 | Likely Benign | 0.458 | Likely Benign | -0.50 | Neutral | 0.734 | Possibly Damaging | 0.138 | Benign | 5.65 | Benign | 1.00 | Tolerated | 0.3395 | 0.5107 | 1 | 1 | -0.1 | -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.740A>G | Q247R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247R is not 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, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain predictions come from premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, 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 | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -4.022 | Likely Benign | 0.442 | Ambiguous | Likely Benign | -0.38 | Likely Benign | 0.0 | 0.21 | Likely Benign | -0.09 | Likely Benign | -0.91 | Ambiguous | 0.471 | Likely Benign | 1.22 | Neutral | 0.948 | Possibly Damaging | 0.533 | Possibly Damaging | 5.91 | Benign | 1.00 | Tolerated | 0.1196 | 0.1324 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| 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.819G>C | E273D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E273D missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only FATHMM predicts a pathogenic outcome, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for E273D, 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 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | -1.811 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.11 | Likely Benign | -0.63 | Ambiguous | 0.094 | Likely Benign | 1.99 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 1.00 | Tolerated | 3.38 | 18 | 0.1711 | 0.1859 | 3 | 2 | 0.0 | -14.03 | 223.1 | 22.1 | 0.2 | 0.0 | 0.0 | 0.1 | X | Potentially Benign | The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated. | ||||||||||||||||||
| c.819G>T | E273D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273D is listed in ClinVar (ID 1471608) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437724‑G‑T). Prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome, while premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | Conflicting | 2 | 6-33437724-G-T | 2 | 1.24e-6 | -1.811 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.11 | Likely Benign | -0.63 | Ambiguous | 0.092 | Likely Benign | 1.99 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 1.00 | Tolerated | 3.38 | 18 | 0.1711 | 0.1859 | 3 | 2 | 0.0 | -14.03 | 223.1 | 22.1 | 0.2 | 0.0 | 0.0 | 0.1 | X | Potentially Benign | The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated. | |||||||||||||
| c.82T>G | S28A 2D AIThe SynGAP1 missense variant S28A 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, derived from a 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 | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -3.517 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.09 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.5194 | 0.4958 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.865A>G | M289V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M289V is reported in ClinVar as Benign (ClinVar ID 2122760.0) and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all predict benign, while only FATHMM predicts pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates benign. No prediction or stability result is inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status and showing no contradiction. 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 | Benign | 1 | -4.239 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.1 | -0.27 | Likely Benign | 0.41 | Likely Benign | 0.24 | Likely Benign | 0.150 | Likely Benign | -0.36 | Neutral | 0.136 | Benign | 0.054 | Benign | 1.80 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | 0.2280 | 0.2808 | 2 | 1 | 2.3 | -32.06 | 204.2 | 51.0 | 0.0 | 0.0 | 0.2 | 0.0 | X | Potentially Benign | The hydrophobic residue Met289, located in a β hairpin linking two anti-parallel β sheet strands (res. Met289-Arg299, res. Arg272-Leu286), is swapped for another hydrophobic residue, valine. In the variant simulations, the branched hydrocarbon side chain of Val289 packs against the phenol group of the Tyr291 side chain but is unable to form methionine-aromatic interactions. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. However, based on the simulations, the residue swap does not cause adverse effects on the structure. | ||||||||||||||||
| c.892C>A | P298T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for P298T, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.366 | In-Between | 0.104 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.24 | Ambiguous | 0.04 | Likely Benign | 0.209 | Likely Benign | -0.13 | Neutral | 0.939 | Possibly Damaging | 0.739 | Possibly Damaging | 1.96 | Pathogenic | 1.00 | Tolerated | 0.1595 | 0.6349 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.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.955G>C | A319P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319P is catalogued in gnomAD (ID 6‑33437860‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive are Rosetta, ESM1b, and Foldetta. 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, 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. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | 6-33437860-G-C | 3 | 1.86e-6 | -7.213 | In-Between | 0.109 | Likely Benign | Likely Benign | -0.02 | Likely Benign | 0.9 | -1.18 | Ambiguous | -0.60 | Ambiguous | 0.22 | Likely Benign | 0.286 | Likely Benign | 0.11 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.97 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | 0.1839 | 0.5067 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.973C>G | L325V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L325V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Rosetta and Foldetta give uncertain results. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -3.104 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 2.26 | Destabilizing | 0.1 | 1.27 | Ambiguous | 1.77 | Ambiguous | -0.39 | Likely Benign | 0.183 | Likely Benign | 0.16 | Neutral | 0.898 | Possibly Damaging | 0.472 | Possibly Damaging | 1.68 | Pathogenic | 1.00 | Tolerated | 0.1571 | 0.3957 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
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