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.2246G>C | R749P 2D  AIThe SynGAP1 missense variant R749P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R749P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -2.467 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.2195 | 0.4878 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>C | S752P 2D  AIThe SynGAP1 missense variant S752P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S752P, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -3.491 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -1.09 | Neutral | 0.998 | Probably Damaging | 0.912 | Probably Damaging | 1.51 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5882 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2272T>A | Y758N 2D  AIThe SynGAP1 missense variant Y758N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.316 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.32 | Neutral | 0.837 | Possibly Damaging | 0.631 | Possibly Damaging | 2.72 | Benign | 0.02 | Affected | 0.2467 | 0.0331 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2272T>C | Y758H 2D  AIThe SynGAP1 missense variant Y758H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.194 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.92 | Neutral | 0.064 | Benign | 0.031 | Benign | 2.71 | Benign | 0.02 | Affected | 0.2519 | 0.0331 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2272T>G | Y758D 2D  AIThe SynGAP1 missense variant Y758D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.688 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -1.89 | Neutral | 0.973 | Probably Damaging | 0.796 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | 0.4647 | 0.0331 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2284G>C | D762H 2D  AIThe SynGAP1 D762H missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.643 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -2.73 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.08 | Pathogenic | 0.02 | Affected | 0.2007 | 0.9102 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2290A>C | N764H 2D  AIThe SynGAP1 missense variant N764H is reported in gnomAD (ID 6‑33441755‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | 6-33441755-A-C | -4.954 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -2.09 | Neutral | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 2.59 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1236 | 0.5056 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||
| c.2292C>A | N764K 2D  AIThe SynGAP1 missense variant N764K is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.867 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.073 | Likely Benign | -1.36 | Neutral | 0.992 | Probably Damaging | 0.921 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.2005 | 0.3539 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2292C>G | N764K 2D AIThe SynGAP1 missense variant N764K is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.867 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.073 | Likely Benign | -1.36 | Neutral | 0.992 | Probably Damaging | 0.921 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.2005 | 0.3539 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>A | S766T 2D  AIThe SynGAP1 missense variant S766T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -4.923 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.25 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1461 | 0.6511 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>G | S766A 2D  AIThe SynGAP1 missense variant S766A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -6.115 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.98 | Neutral | 0.447 | Benign | 0.198 | Benign | 4.17 | Benign | 0.02 | Affected | 0.5059 | 0.5705 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2303A>T | D768V 2D  AIThe SynGAP1 D768V variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -9.528 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -2.62 | Deleterious | 0.611 | Possibly Damaging | 0.140 | Benign | 4.04 | Benign | 0.02 | Affected | 0.0802 | 0.8019 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2305C>T | L769F 2D  AIThe SynGAP1 missense variant L769F is listed in ClinVar (ID 3617309.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions—including the high‑accuracy tools—suggest the variant is most likely benign, which is consistent with its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | Uncertain | 1 | -5.044 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.89 | Neutral | 0.925 | Possibly Damaging | 0.510 | Possibly Damaging | 3.94 | Benign | 0.02 | Affected | 0.0554 | 0.2881 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.2309A>C | Q770P 2D  AIThe SynGAP1 missense variant Q770P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q770P, 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -3.948 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -1.00 | Neutral | 0.748 | Possibly Damaging | 0.170 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2435 | 0.5717 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2318T>A | M773K 2D  AIThe SynGAP1 missense variant M773K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar, SIFT, 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 results are unavailable. 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -5.117 | Likely Benign | 0.641 | Likely Pathogenic | Likely Benign | 0.178 | Likely Benign | -1.80 | Neutral | 0.106 | Benign | 0.471 | Possibly Damaging | 4.19 | Benign | 0.02 | Affected | 0.1646 | 0.0851 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2318T>G | M773R 2D  AIThe SynGAP1 missense variant M773R is listed in gnomAD (ID 6‑33442476‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by ClinVar status, which is currently absent. 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 | 6-33442476-T-G | 1 | 1.28e-6 | -4.340 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | -1.87 | Neutral | 0.220 | Benign | 0.471 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1778 | 0.0800 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||
| c.2329C>A | L777I 2D  AIThe SynGAP1 missense variant L777I is listed in gnomAD (ID 6‑33442487‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports “Likely Benign.” Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | 6-33442487-C-A | -5.346 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.843 | Possibly Damaging | 0.920 | Probably Damaging | 4.05 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1041 | 0.4327 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.2332A>T | N778Y 2D  AIThe SynGAP1 missense variant N778Y is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). AlphaMissense‑Default is uncertain, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -5.723 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -2.48 | Neutral | 0.991 | Probably Damaging | 0.980 | Probably Damaging | 4.16 | Benign | 0.02 | Affected | 0.0589 | 0.6139 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2333A>T | N778I 2D  AIThe SynGAP1 missense variant N778I is reported in gnomAD (ID 6‑33442491‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy predictors) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442491-A-T | -6.659 | Likely Benign | 0.622 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | -2.48 | Neutral | 0.991 | Probably Damaging | 0.980 | Probably Damaging | 4.17 | Benign | 0.02 | Affected | 3.64 | 6 | 0.0628 | 0.6128 | -3 | -2 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.2344G>A | D782N 2D  AIThe SynGAP1 missense variant D782N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -6.857 | Likely Benign | 0.766 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -2.26 | Neutral | 0.995 | Probably Damaging | 0.950 | Probably Damaging | 1.98 | Pathogenic | 0.02 | Affected | 0.1167 | 0.6884 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2345A>G | D782G 2D  AIThe SynGAP1 missense variant D782G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -6.811 | Likely Benign | 0.858 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.27 | Deleterious | 0.995 | Probably Damaging | 0.950 | Probably Damaging | 1.95 | Pathogenic | 0.02 | Affected | 0.3816 | 0.6318 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2359C>G | P787A 2D  AIThe SynGAP1 P787A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM) predict a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic versus three benign predictions, with the SGM Consensus supporting pathogenicity—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -4.542 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -4.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 0.3425 | 0.4444 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2359C>T | P787S 2D  AIThe SynGAP1 P787S variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442911‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | Uncertain | 1 | 6-33442911-C-T | 3 | 1.86e-6 | -4.203 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.221 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.3420 | 0.4675 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2362T>A | S788T 2D AIThe SynGAP1 missense variant S788T is listed in ClinVar with an uncertain significance (ClinVar ID 392728.0) and is present in the gnomAD database (gnomAD ID 6‑33442914‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote) also favors a benign interpretation. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | Uncertain | 2 | 6-33442914-T-A | 4 | 2.49e-6 | -4.288 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -2.25 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 1.55 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.1794 | 0.6339 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||
| c.2362T>G | S788A 2D AIThe SynGAP1 missense variant S788A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for S788A. This consensus does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | -5.381 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -2.24 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 1.59 | Pathogenic | 0.02 | Affected | 0.5079 | 0.5041 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||
| c.2368A>G | T790A 2D  AIThe SynGAP1 T790A missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, while the SGM Consensus remains inconclusive and Foldetta data are unavailable. Overall, the majority of standard predictors indicate pathogenicity, but the single high‑accuracy tool that is available suggests a benign effect, and no high‑accuracy tool provides a definitive pathogenic verdict. Consequently, the variant is most likely pathogenic according to the bulk of predictions, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | -4.337 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.64 | Deleterious | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.35 | Pathogenic | 0.02 | Affected | 0.4157 | 0.4207 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2369C>A | T790N 2D  AIThe SynGAP1 missense variant T790N is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33442921‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable, and Foldetta results are not reported. Overall, the majority of conventional tools (5 pathogenic vs. 4 benign) lean toward a pathogenic interpretation, while the single high‑accuracy tool suggests benign. The variant’s ClinVar status remains uncertain, so there is no contradiction with the current clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | Conflicting | 3 | 6-33442921-C-A | 69 | 4.28e-5 | -5.243 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -2.54 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.27 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.1446 | 0.4653 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||
| c.2374G>C | E792Q 2D  AIThe SynGAP1 missense variant E792Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” verdict, reflecting the majority of benign calls. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that E792Q is most likely benign, 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 | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | -3.782 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.052 | Likely Benign | -1.60 | Neutral | 0.077 | Benign | 0.049 | Benign | 3.89 | Benign | 0.02 | Affected | 0.1469 | 0.7401 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.2381C>A | P794Q 2D  AIThe SynGAP1 missense variant P794Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P794Q, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -4.641 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.31 | Neutral | 0.918 | Possibly Damaging | 0.601 | Possibly Damaging | 4.24 | Benign | 0.02 | Affected | 0.1581 | 0.4971 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2381C>G | P794R 2D  AIThe SynGAP1 missense variant P794R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P794R, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -5.136 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.73 | Neutral | 0.918 | Possibly Damaging | 0.522 | Possibly Damaging | 4.25 | Benign | 0.02 | Affected | 0.1467 | 0.3662 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2405G>C | G802A 2D  AIThe SynGAP1 missense variant G802A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G802A is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -3.584 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.089 | Benign | 2.74 | Benign | 0.02 | Affected | 0.3779 | 0.4554 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2416T>G | F806V 2D  AIThe SynGAP1 missense variant F806V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; a Foldetta stability analysis is unavailable. Overall, the balance of evidence from the majority of prediction algorithms points to a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -4.548 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -3.79 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.16 | Pathogenic | 0.02 | Affected | 0.2464 | 0.1325 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||
| c.2425A>G | S809G 2D  AIThe SynGAP1 missense variant S809G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the preponderance of evidence indicates that S809G is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -6.100 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.80 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.61 | Benign | 0.02 | Affected | 0.2743 | 0.5369 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2443C>A | R815S 2D  AISynGAP1 R815S is listed in ClinVar as Benign (ID 3645150.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus as Benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of predictions lean toward pathogenicity, whereas the consensus and high‑accuracy tools suggest benignity. Thus, the variant is most likely pathogenic based on the prevailing predictions, contradicting its ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Benign | 1 | -7.324 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | -1.86 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | 0.2937 | 0.4164 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.2443C>G | R815G 2D  AISynGAP1 missense variant R815G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on benign effect include REVEL and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Uncertain calls are made by ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -7.983 | In-Between | 0.854 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -3.22 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.02 | Affected | 4.32 | 4 | 0.3481 | 0.4015 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2444G>A | R815H 2D  AIThe SynGAP1 missense variant R815H (ClinVar ID 833773.0) is classified as benign in ClinVar and is present in gnomAD (6‑33442996‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools report uncertainty: ESM1b and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta stability assessment are unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and with no conflict regarding its status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Likely Benign | 2 | 6-33442996-G-A | 24 | 1.49e-5 | -7.474 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 4.32 | 4 | 0.2944 | 0.2281 | 2 | 0 | 1.3 | -19.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2444G>C | R815P 2D AIThe SynGAP1 missense variant R815P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic; AlphaMissense‑Optimized remains uncertain, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates that R815P is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | -7.495 | In-Between | 0.858 | Likely Pathogenic | Ambiguous | 0.153 | Likely Benign | -2.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.2113 | 0.4897 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2452C>A | P818T 2D  AIThe SynGAP1 missense variant P818T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -6.864 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.265 | Likely Benign | -4.58 | Deleterious | 0.994 | Probably Damaging | 0.927 | Probably Damaging | 2.01 | Pathogenic | 0.02 | Affected | 0.1797 | 0.6453 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2453C>T | P818L 2D  AIThe SynGAP1 missense variant P818L is catalogued in gnomAD (ID 6‑33443005‑C‑T) but has no ClinVar entry. Functional prediction tools fall into two consensus groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessments are limited: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates “Likely Pathogenic,” and Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely pathogenic based on current predictive tools. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | 6-33443005-C-T | 1 | 6.20e-7 | -6.064 | Likely Benign | 0.938 | Likely Pathogenic | Ambiguous | 0.285 | Likely Benign | -5.81 | Deleterious | 0.997 | Probably Damaging | 0.954 | Probably Damaging | 1.98 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2351 | 0.6951 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2473T>C | S825P 2D AIThe SynGAP1 missense variant S825P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S825P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -3.227 | Likely Benign | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | -3.12 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 0.2060 | 0.5998 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2477A>C | D826A 2D  AIThe SynGAP1 D826A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -5.590 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.307 | Likely Benign | -3.77 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.53 | Benign | 0.02 | Affected | 0.4463 | 0.7867 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2488C>A | P830T 2D AIThe SynGAP1 missense variant P830T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for P830T, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.618152 | Binding | 0.333 | 0.874 | 0.500 | -4.697 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.222 | Likely Benign | -3.56 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | 0.1519 | 0.5970 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2492A>T | E831V 2D  AIThe SynGAP1 missense variant E831V is not reported in ClinVar and has no gnomAD allele. Prediction tools show a split: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts a benign effect, SGM‑Consensus indicates a likely pathogenic outcome, and Foldetta data are unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.626927 | Disordered | 0.617732 | Binding | 0.319 | 0.874 | 0.375 | -6.327 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.204 | Likely Benign | -3.43 | Deleterious | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 2.32 | Pathogenic | 0.02 | Affected | 0.0604 | 0.7407 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2498A>C | K833T 2D  AIThe SynGAP1 missense variant K833T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate predictions, K833T 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 | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -1.741 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.65 | Neutral | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 0.1848 | 0.3335 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2499G>C | K833N 2D  AIThe SynGAP1 missense variant K833N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation. This conclusion is consistent with the lack of a ClinVar assertion, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.759 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.02 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.3088 | 0.1464 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2499G>T | K833N 2D AIThe SynGAP1 missense variant K833N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for K833N, 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 | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.759 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.02 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.3088 | 0.1464 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2504T>A | L835Q 2D  AIThe SynGAP1 missense variant L835Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are not available, so they do not influence the overall assessment. Based on the majority of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | -4.788 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.84 | Neutral | 0.996 | Probably Damaging | 0.967 | Probably Damaging | 2.70 | Benign | 0.02 | Affected | 0.1033 | 0.1162 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2504T>G | L835R 2D  AIThe SynGAP1 missense variant L835R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | -4.749 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.05 | Neutral | 0.996 | Probably Damaging | 0.955 | Probably Damaging | 2.70 | Benign | 0.02 | Affected | 0.1239 | 0.0804 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2515A>C | K839Q 2D  AIThe SynGAP1 missense variant K839Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions and the consensus call indicate a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -10.631 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -1.98 | Neutral | 0.972 | Probably Damaging | 0.862 | Possibly Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.4544 | 0.1437 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2521G>A | V841M 2D  AISynGAP1 variant V841M is listed in ClinVar with an uncertain significance and is present in gnomAD (6-33443073-G-A). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The ESM1b score is inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta stability analysis is unavailable. Taken together, the majority of evidence, including the high‑accuracy tools, points to a benign effect for V841M. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | Uncertain | 1 | 6-33443073-G-A | 3 | 1.86e-6 | -7.000 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.119 | Likely Benign | -0.74 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0707 | 0.3937 | 1 | 2 | -2.3 | 32.06 | |||||||||||||||||||||||||||||||||
| c.2522T>C | V841A 2D  AIThe SynGAP1 missense variant V841A (ClinVar ID 1395978.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443074‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool reports an uncertain outcome, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (two pathogenic, two benign) and is therefore inconclusive. No Foldetta stability assessment is available for this variant. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the current ClinVar designation of Uncertain. 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 | Uncertain | 1 | 6-33443074-T-C | 3 | 1.86e-6 | -8.152 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.183 | Likely Benign | -2.13 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.57 | Benign | 0.02 | Affected | 3.77 | 5 | 0.3069 | 0.2106 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||
| c.2543G>T | G848V 2D  AIThe SynGAP1 missense variant G848V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443095‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | 6-33443095-G-T | 1 | 6.20e-7 | -4.445 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1184 | 0.4336 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.2549G>A | G850E 2D  AIThe SynGAP1 missense variant G850E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation. The variant is most likely benign based on predictions, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -4.052 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -0.60 | Neutral | 0.770 | Possibly Damaging | 0.327 | Benign | 4.28 | Benign | 0.02 | Affected | 0.1612 | 0.4232 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2549G>T | G850V 2D AIThe SynGAP1 missense variant G850V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools converge on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for G850V, 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 | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -5.379 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -1.74 | Neutral | 0.960 | Probably Damaging | 0.679 | Possibly Damaging | 4.21 | Benign | 0.02 | Affected | 0.1255 | 0.4077 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2555G>T | G852V 2D AIThe SynGAP1 missense variant G852V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G852V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -5.629 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.30 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.19 | Benign | 0.02 | Affected | 0.1205 | 0.4173 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2557G>A | G853S 2D  AIThe SynGAP1 missense variant G853S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G853S 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 | 0.657645 | Disordered | 0.496246 | Uncertain | 0.284 | 0.815 | 0.625 | -3.878 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.155 | Likely Benign | 0.14 | Neutral | 0.003 | Benign | 0.008 | Benign | 4.31 | Benign | 0.02 | Affected | 0.2783 | 0.5206 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2572A>C | S858R 2D  AIThe SynGAP1 missense variant S858R is reported in ClinVar as “None” and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -3.924 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -1.18 | Neutral | 0.818 | Possibly Damaging | 0.899 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0996 | 0.3778 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2572A>T | S858C 2D  AIThe SynGAP1 missense variant S858C is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion 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 | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -6.767 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -1.93 | Neutral | 0.940 | Possibly Damaging | 0.979 | Probably Damaging | 4.06 | Benign | 0.02 | Affected | 0.1206 | 0.6155 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2573G>A | S858N 2D  AIThe SynGAP1 missense variant S858N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443125‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign. In contrast, polyPhen‑2 HumVar and SIFT predict pathogenicity, but these two tools are in the minority. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | Uncertain | 1 | 6-33443125-G-A | 2 | 1.24e-6 | -4.311 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -0.67 | Neutral | 0.448 | Benign | 0.846 | Possibly Damaging | 4.13 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1527 | 0.4772 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
| c.2574C>A | S858R 2D AIThe SynGAP1 missense variant S858R is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -3.924 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -1.18 | Neutral | 0.818 | Possibly Damaging | 0.899 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0996 | 0.3778 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2574C>G | S858R 2D AIThe SynGAP1 missense variant S858R is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -3.924 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -1.18 | Neutral | 0.818 | Possibly Damaging | 0.899 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0996 | 0.3778 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2576G>T | S859I 2D  AIThe SynGAP1 missense variant S859I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of computational evidence indicates a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar record exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -8.342 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.256 | Likely Benign | -1.94 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 3.99 | Benign | 0.02 | Affected | 0.1094 | 0.5867 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2609T>A | L870Q 2D AIThe SynGAP1 missense variant L870Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus itself is labeled likely benign. No output is available from the Foldetta stability analysis, so it does not influence the overall assessment. Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.029 | Likely Benign | 0.417 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -1.90 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1027 | 0.1003 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>G | L870R 2D AIThe SynGAP1 missense variant L870R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L870R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.578 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | 0.175 | Likely Benign | -1.97 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1147 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>T | S873I 2D AIThe SynGAP1 missense variant S873I has no ClinVar record and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of other in‑silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this residue. High‑accuracy assessment therefore points to a Likely Pathogenic status from SGM‑Consensus, with AlphaMissense‑Optimized inconclusive and Foldetta missing. Overall, the preponderance of evidence suggests the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -9.412 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | -3.44 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.1012 | 0.5560 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2624C>A | A875D 2D  AIThe SynGAP1 missense variant A875D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2) and Foldetta data are unavailable. Overall, the majority of standard tools (5 pathogenic vs 4 benign) lean toward a pathogenic interpretation, but the high‑accuracy predictions are mixed or missing. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -3.268 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | -2.78 | Deleterious | 0.992 | Probably Damaging | 0.913 | Probably Damaging | 2.68 | Benign | 0.02 | Affected | 0.1648 | 0.2035 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2630T>G | L877R 2D AIThe SynGAP1 missense variant L877R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -6.678 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.148 | Likely Benign | -1.82 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 0.1218 | 0.0761 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2643G>C | L881F 2D AIThe SynGAP1 missense variant L881F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for L881F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -5.759 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.87 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.0711 | 0.3415 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2643G>T | L881F 2D AIThe SynGAP1 missense variant L881F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for L881F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -5.759 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.87 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.0711 | 0.3415 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2645G>T | G882V 2D AIThe SynGAP1 missense variant G882V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -5.893 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -2.41 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.06 | Pathogenic | 0.02 | Affected | 0.1178 | 0.4717 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2665G>A | G889R 2D  AIThe SynGAP1 missense variant G889R is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33443217‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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 impact. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | 6-33443217-G-A | 1 | 6.20e-7 | -3.357 | Likely Benign | 0.685 | Likely Pathogenic | Likely Benign | 0.070 | Likely Benign | -1.96 | Neutral | 0.027 | Benign | 0.009 | Benign | 2.38 | Pathogenic | 0.02 | Affected | 4.32 | 4 | 0.0925 | 0.4165 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2665G>C | G889R 2D AIThe SynGAP1 missense variant G889R is not reported in ClinVar (ClinVar status: not present) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), 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 based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | -3.357 | Likely Benign | 0.685 | Likely Pathogenic | Likely Benign | 0.072 | Likely Benign | -1.96 | Neutral | 0.027 | Benign | 0.009 | Benign | 2.38 | Pathogenic | 0.02 | Affected | 4.32 | 4 | 0.0925 | 0.4165 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2666G>A | G889E 2D AIThe SynGAP1 missense variant G889E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | -5.352 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.083 | Likely Benign | -1.96 | Neutral | 0.611 | Possibly Damaging | 0.187 | Benign | 2.41 | Pathogenic | 0.02 | Affected | 0.1442 | 0.3719 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2674T>G | S892A 2D AIThe SynGAP1 missense variant S892A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -3.867 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.45 | Neutral | 0.889 | Possibly Damaging | 0.682 | Possibly Damaging | 2.63 | Benign | 0.02 | Affected | 0.5131 | 0.4481 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2681G>T | G894V 2D AIThe SynGAP1 missense variant G894V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with the 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. | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -5.047 | Likely Benign | 0.395 | Ambiguous | Likely Benign | 0.188 | Likely Benign | -2.61 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1187 | 0.4091 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2707G>C | G903R 2D AIThe SynGAP1 missense variant G903R is not 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, and ESM1b. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and no ClinVar annotation contradicts this assessment. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -3.503 | Likely Benign | 0.865 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -2.02 | Neutral | 0.241 | Benign | 0.244 | Benign | 2.33 | Pathogenic | 0.02 | Affected | 0.0872 | 0.4064 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2707G>T | G903C 2D  AIThe SynGAP1 missense variant G903C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain and does not influence the consensus. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, which would provide a protein‑folding stability estimate, is unavailable for this variant. Overall, the majority of evidence (five pathogenic versus three benign predictions) points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -6.593 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -3.28 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 2.32 | Pathogenic | 0.02 | Affected | 0.1158 | 0.4420 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2717T>A | L906H 2D  AIThe SynGAP1 missense variant L906H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs. two pathogenic votes) and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, but the most reliable high‑accuracy tool suggests a benign outcome and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -4.367 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | -1.01 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.18 | Pathogenic | 0.02 | Affected | 0.1125 | 0.1073 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2719A>T | S907C 2D AIThe SynGAP1 missense variant S907C is listed in ClinVar as Benign (ClinVar ID 1502069.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification and indicating no contradiction with the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | Likely Benign | 1 | -6.685 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.34 | Neutral | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1023 | 0.5951 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2728G>C | G910R 2D AIThe SynGAP1 missense variant G910R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -4.566 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.235 | Likely Benign | -1.78 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.02 | Affected | 0.0875 | 0.4198 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2729G>T | G910V 2D AIThe SynGAP1 missense variant G910V is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443281‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) predict a pathogenic impact. This prediction does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | 6-33443281-G-T | 1 | 6.20e-7 | -4.362 | Likely Benign | 0.724 | Likely Pathogenic | Likely Benign | 0.237 | Likely Benign | -2.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.73 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1179 | 0.3662 | -3 | -1 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.2740G>A | D914N 2D AIThe SynGAP1 missense variant D914N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.859 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -1.22 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 0.1770 | 0.7848 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2741A>G | D914G 2D AIThe SynGAP1 missense variant D914G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for D914G, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -1.486 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.46 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.4421 | 0.7257 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2746G>T | V916F 2D  AIThe SynGAP1 missense variant V916F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -4.011 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.18 | Neutral | 0.642 | Possibly Damaging | 0.265 | Benign | 2.67 | Benign | 0.02 | Affected | 0.0729 | 0.4593 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2761C>A | L921M 2D  AIThe SynGAP1 missense variant L921M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for L921M, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -4.485 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.38 | Neutral | 0.489 | Possibly Damaging | 0.137 | Benign | 2.40 | Pathogenic | 0.02 | Affected | 0.0762 | 0.3732 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2798A>C | H933P 2D  AIThe SynGAP1 missense variant H933P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, six tools predict pathogenicity versus three predicting benign, and the high‑accuracy benign prediction is outweighed by the majority of pathogenic calls. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -3.890 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.508 | Likely Pathogenic | -5.39 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.36 | Pathogenic | 0.02 | Affected | 0.1821 | 0.4400 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2798A>T | H933L 2D  AIThe SynGAP1 H933L missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -0.858 | Likely Benign | 0.470 | Ambiguous | Likely Benign | 0.388 | Likely Benign | -6.26 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0.1003 | 0.5749 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2807C>A | A936D 2D AIThe SynGAP1 missense variant A936D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.973218 | Binding | 0.319 | 0.874 | 0.625 | -4.162 | Likely Benign | 0.686 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.63 | Neutral | 0.801 | Possibly Damaging | 0.339 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.1778 | 0.1660 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2810A>T | D937V 2D AIThe SynGAP1 missense variant D937V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. This consensus does not contradict ClinVar status, as no ClinVar entry exists for this variant. Thus, based on current computational evidence, the D937V variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -3.418 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -2.21 | Neutral | 1.000 | Probably Damaging | 0.977 | Probably Damaging | 2.70 | Benign | 0.02 | Affected | 0.1766 | 0.7408 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2846G>A | G949D 2D  AIThe SynGAP1 missense variant G949D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (5 pathogenic vs. 4 benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -8.692 | Likely Pathogenic | 0.239 | Likely Benign | Likely Benign | 0.316 | Likely Benign | 0.25 | Neutral | 0.945 | Possibly Damaging | 0.753 | Possibly Damaging | 2.21 | Pathogenic | 0.02 | Affected | 0.1927 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2849G>A | G950D 2D AIThe SynGAP1 missense variant G950D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -7.515 | In-Between | 0.245 | Likely Benign | Likely Benign | 0.402 | Likely Benign | -0.61 | Neutral | 0.411 | Benign | 0.131 | Benign | 2.26 | Pathogenic | 0.02 | Affected | 0.1874 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2854G>C | G952R 2D AIThe SynGAP1 missense variant G952R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G952R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.974 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.077 | Benign | 0.011 | Benign | 3.20 | Benign | 0.02 | Affected | 0.1145 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2855G>T | G952V 2D AIThe SynGAP1 missense variant G952V is listed in ClinVar (ID 2055482.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b 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 is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that G952V is most likely benign, 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 | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | Uncertain | 1 | -7.074 | In-Between | 0.078 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -0.33 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.20 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1538 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.2882A>C | H961P 2D AIThe SynGAP1 missense variant H961P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while only SIFT and ESM1b predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a Likely Benign verdict (3 benign vs. 1 pathogenic). High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Consequently, the collective evidence indicates that H961P is most likely benign, 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 | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | -8.434 | Likely Pathogenic | 0.071 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.58 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.02 | Affected | 0.2061 | 0.4701 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2882A>G | H961R 2D  AIThe SynGAP1 missense variant H961R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (3 benign vs. 1 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 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 | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | -9.258 | Likely Pathogenic | 0.189 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.90 | Neutral | 0.144 | Benign | 0.078 | Benign | 4.16 | Benign | 0.02 | Affected | 0.2201 | 0.3267 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.2883C>A | H961Q 2D  AIThe SynGAP1 missense variant H961Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT and ESM1b predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict (3 benign vs. 1 pathogenic). High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the 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 | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | -8.368 | Likely Pathogenic | 0.118 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.49 | Neutral | 0.255 | Benign | 0.105 | Benign | 4.17 | Benign | 0.02 | Affected | 0.2022 | 0.3743 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2883C>G | H961Q 2D AIThe SynGAP1 missense variant H961Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as “Likely Benign.” High‑accuracy assessments reinforce this view: 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 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 | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | -8.368 | Likely Pathogenic | 0.118 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.49 | Neutral | 0.255 | Benign | 0.105 | Benign | 4.17 | Benign | 0.02 | Affected | 0.2022 | 0.3743 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2890C>T | H964Y 2D  AIThe SynGAP1 missense variant H964Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and the Foldetta stability analysis is unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.990547 | Disordered | 0.982486 | Binding | 0.364 | 0.886 | 0.750 | -7.385 | In-Between | 0.139 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.13 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.11 | Benign | 0.02 | Affected | 0.1422 | 0.4363 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2891A>T | H964L 2D AIThe SynGAP1 missense variant H964L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) indicates likely benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.990547 | Disordered | 0.982486 | Binding | 0.364 | 0.886 | 0.750 | -7.568 | In-Between | 0.092 | Likely Benign | Likely Benign | 0.129 | Likely Benign | -1.20 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1409 | 0.5195 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2915C>A | P972H 2D  AIThe SynGAP1 missense variant P972H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments 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 consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, 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 | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.791 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.62 | Neutral | 0.589 | Possibly Damaging | 0.229 | Benign | 4.19 | Benign | 0.02 | Affected | 0.1930 | 0.4798 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2915C>T | P972L 2D AIThe SynGAP1 missense variant P972L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.399 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -1.73 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.24 | Benign | 0.02 | Affected | 0.2107 | 0.5447 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2920G>C | D974H 2D AIThe SynGAP1 missense variant D974H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.034 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.95 | Neutral | 0.744 | Possibly Damaging | 0.382 | Benign | 4.14 | Benign | 0.02 | Affected | 0.2249 | 0.7803 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2929G>A | A977T 2D  AIThe SynGAP1 missense variant A977T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -3.814 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.84 | Neutral | 0.965 | Probably Damaging | 0.782 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 0.2155 | 0.6185 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2929G>C | A977P 2D  AIThe SynGAP1 missense variant A977P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A977P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.665 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -1.12 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 3.94 | Benign | 0.02 | Affected | 0.2405 | 0.5212 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2959G>C | D987H 2D AIThe SynGAP1 missense variant D987H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -5.580 | Likely Benign | 0.925 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -3.16 | Deleterious | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.35 | Pathogenic | 0.02 | Affected | 0.1553 | 0.7629 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2960A>C | D987A 2D AIThe SynGAP1 D987A missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools that classify the change as benign include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) and the SGM‑Consensus score (Likely Pathogenic) indicate a pathogenic effect. Grouping by agreement, benign predictions are limited to two tools, while pathogenic predictions are supported by seven distinct algorithms. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a Likely Pathogenic classification, and the protein‑folding stability method Foldetta is unavailable for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.880 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.261 | Likely Benign | -3.72 | Deleterious | 0.943 | Possibly Damaging | 0.686 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 0.3930 | 0.6846 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2980A>G | K994E 2D  AIThe SynGAP1 missense variant K994E is reported in gnomAD (variant ID 6‑33443532‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. This prediction does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | 6-33443532-A-G | 1 | 6.20e-7 | -2.587 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.14 | Benign | 0.02 | Affected | 4.32 | 2 | 0.4148 | 0.1699 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||
| c.2987C>T | P996L 2D AIThe SynGAP1 missense variant P996L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -5.302 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.65 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.25 | Benign | 0.02 | Affected | 0.2057 | 0.6631 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3025G>C | E1009Q 2D AIThe SynGAP1 missense variant E1009Q is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33443577‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | 6-33443577-G-C | 1 | 6.20e-7 | -3.423 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -1.65 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1577 | 0.7242 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3047A>C | D1016A 2D AIThe SynGAP1 D1016A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the functional impact uncertain. **Based on the current predictions, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which has no entry for this variant.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -2.120 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.248 | Likely Benign | -2.71 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 2.50 | Benign | 0.02 | Affected | 0.4040 | 0.6760 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3052A>C | T1018P 2D  AIThe SynGAP1 missense variant T1018P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.046 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 2.24 | Pathogenic | 0.02 | Affected | 0.2155 | 0.3960 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>C | Q1021P 2D AIThe SynGAP1 missense variant Q1021P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1021P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -3.522 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -2.11 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.56 | Benign | 0.02 | Affected | 0.2022 | 0.4789 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3067T>C | S1023P 2D AIThe SynGAP1 missense variant S1023P is reported in gnomAD (ID 6‑33443619‑T‑C) but has no ClinVar entry (ClinVar status: not reported). Functional prediction tools are split: benign calls come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of standard predictors lean toward pathogenicity, whereas the few high‑accuracy tools do not support a pathogenic verdict. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | 6-33443619-T-C | 2 | 1.24e-6 | -5.634 | Likely Benign | 0.679 | Likely Pathogenic | Likely Benign | 0.146 | Likely Benign | -2.11 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.43 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1818 | 0.4616 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3071T>G | L1024R 2D AIThe SynGAP1 missense variant L1024R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.434 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | -2.41 | Neutral | 0.997 | Probably Damaging | 0.962 | Probably Damaging | 2.40 | Pathogenic | 0.02 | Affected | 0.1335 | 0.1557 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3077A>C | D1026A 2D AIThe SynGAP1 D1026A variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie, and Foldetta results are not available. Overall, the majority of standard tools favor a benign interpretation, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.211 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.070 | Likely Benign | -2.69 | Deleterious | 0.112 | Benign | 0.061 | Benign | 2.53 | Benign | 0.02 | Affected | 0.3392 | 0.5279 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3080A>T | N1027I 2D AIThe SynGAP1 missense variant N1027I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.847 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | -2.36 | Neutral | 0.970 | Probably Damaging | 0.726 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | 0.0677 | 0.5724 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>C | H1030P 2D AIThe SynGAP1 missense variant H1030P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that H1030P 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.185 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -0.78 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.77 | Benign | 0.02 | Affected | 0.1872 | 0.4225 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>T | H1030L 2D AIThe SynGAP1 missense variant H1030L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that H1030L is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.513 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -2.35 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.02 | Affected | 0.0968 | 0.5710 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3095T>G | L1032R 2D AIThe SynGAP1 missense variant L1032R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.658 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -1.03 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | 0.1350 | 0.1919 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3101C>A | P1034H 2D AIThe SynGAP1 missense variant P1034H is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.634 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.083 | Likely Benign | -3.17 | Deleterious | 0.938 | Possibly Damaging | 0.750 | Possibly Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0.1776 | 0.5451 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3101C>G | P1034R 2D AIThe SynGAP1 P1034R variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the predictions are mixed, with a slight tilt toward pathogenicity due to the SGM Consensus result and the number of pathogenic calls. The variant is most likely pathogenic based on the current computational evidence, 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. | Likely Pathogenic | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -3.666 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.073 | Likely Benign | -3.04 | Deleterious | 0.002 | Benign | 0.005 | Benign | 2.40 | Pathogenic | 0.02 | Affected | 0.1366 | 0.4182 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3116T>A | I1039N 2D  AIThe SynGAP1 missense variant I1039N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates 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. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none is present). 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 | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -3.469 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.24 | Neutral | 0.011 | Benign | 0.010 | Benign | 2.67 | Benign | 0.02 | Affected | 0.1151 | 0.1311 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3118G>A | G1040S 2D AIThe SynGAP1 missense variant G1040S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence (six benign versus four pathogenic predictions) points to a benign impact for G1040S. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.179 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.653 | Likely Pathogenic | -1.81 | Neutral | 0.827 | Possibly Damaging | 0.375 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.2332 | 0.5298 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3140C>T | S1047L 2D  AIThe SynGAP1 missense variant S1047L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443692‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of computational evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | Uncertain | 1 | 6-33443692-C-T | 1 | 6.20e-7 | -4.062 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -0.63 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1575 | 0.5555 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.3142G>T | G1048W 2D  AIThe SynGAP1 missense variant G1048W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -8.803 | Likely Pathogenic | 0.340 | Likely Benign | Likely Benign | 0.498 | Likely Benign | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0852 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3145C>A | P1049T 2D AIThe SynGAP1 missense variant P1049T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta results are unavailable, so no additional stability evidence is present. Overall, the consensus of available predictions indicates that P1049T 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. | Likely Benign | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.100 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.18 | Neutral | 0.519 | Possibly Damaging | 0.222 | Benign | 2.74 | Benign | 0.02 | Affected | 0.1791 | 0.5514 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3146C>T | P1049L 2D AIThe SynGAP1 missense variant P1049L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -4.819 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -2.37 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.71 | Benign | 0.02 | Affected | 0.2267 | 0.5838 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3154G>T | G1052W 2D AIThe SynGAP1 missense variant G1052W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -11.322 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.457 | Likely Benign | -0.90 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.0872 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3215A>T | K1072M 2D  AIThe SynGAP1 K1072M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -2.821 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -1.37 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.88 | Benign | 0.02 | Affected | 0.1266 | 0.4877 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3217T>G | S1073A 2D AIThe SynGAP1 missense variant S1073A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) confirms a benign status. Foldetta’s protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools suggests 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 | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -5.333 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.96 | Neutral | 0.447 | Benign | 0.103 | Benign | 3.95 | Benign | 0.02 | Affected | 0.4571 | 0.5883 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3227T>G | L1076W 2D  AIThe SynGAP1 missense variant L1076W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -6.377 | Likely Benign | 0.822 | Likely Pathogenic | Ambiguous | 0.183 | Likely Benign | -1.40 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0.0749 | 0.3740 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3232G>T | V1078F 2D AIThe SynGAP1 missense variant V1078F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for V1078F, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.768 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -0.97 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 3.87 | Benign | 0.02 | Affected | 0.0677 | 0.4561 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3233T>C | V1078A 2D AIThe SynGAP1 missense variant V1078A is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of predictions indicate that V1078A 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 | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.794 | Likely Benign | 0.690 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.27 | Neutral | 0.011 | Benign | 0.006 | Benign | 3.94 | Benign | 0.02 | Affected | 0.2679 | 0.2546 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3238G>C | A1080P 2D AIThe SynGAP1 missense variant A1080P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A1080P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -2.429 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.15 | Neutral | 0.996 | Probably Damaging | 0.833 | Possibly Damaging | 3.96 | Benign | 0.02 | Affected | 0.1884 | 0.5324 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3254G>A | R1085Q 2D  AIThe SynGAP1 missense variant R1085Q (ClinVar ID 1729448.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33443806‑G‑A). Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also favors benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to 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 | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | Uncertain | 1 | 6-33443806-G-A | 5 | 3.16e-6 | -3.843 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.224 | Likely Benign | -1.43 | Neutral | 0.998 | Probably Damaging | 0.988 | Probably Damaging | 2.73 | Benign | 0.02 | Affected | 3.77 | 5 | 0.2962 | 0.2751 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3260C>A | S1087Y 2D  AIThe SynGAP1 missense variant S1087Y is catalogued in gnomAD (ID 6‑33443812‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-A | -4.194 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.41 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0671 | 0.5845 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.3263G>A | S1088N 2D AIThe SynGAP1 missense variant S1088N has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM‑Consensus (derived from the four high‑accuracy tools) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a benign impact, and this assessment 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 | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -5.227 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.25 | Neutral | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 0.1940 | 0.5197 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3266G>C | G1089A 2D AIThe SynGAP1 missense variant G1089A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -2.864 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.73 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.45 | Pathogenic | 0.02 | Affected | 0.3475 | 0.5331 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>T | N1090I 2D AIThe SynGAP1 missense variant N1090I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign classification, 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 | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -4.356 | Likely Benign | 0.765 | Likely Pathogenic | Likely Benign | 0.173 | Likely Benign | -2.14 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | 0.0781 | 0.6279 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3272T>A | L1091Q 2D AIThe SynGAP1 missense variant L1091Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -4.381 | Likely Benign | 0.854 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.32 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.1192 | 0.1514 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3272T>G | L1091R 2D AIThe SynGAP1 missense variant L1091R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of consensus tools (five pathogenic vs. three benign) suggest a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -3.662 | Likely Benign | 0.896 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | -1.51 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.1274 | 0.1357 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3279G>C | Q1093H 2D  AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1600 | 0.5269 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3279G>T | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1600 | 0.5269 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3281C>A | S1094Y 2D AIThe SynGAP1 missense variant S1094Y is not reported in ClinVar (status: none) but is present in gnomAD (ID 6‑33443833‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show a benign call from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the balance of evidence leans toward a pathogenic interpretation (five pathogenic versus four benign calls), and this does not contradict the ClinVar status, which currently has no assertion for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | 6-33443833-C-A | -5.609 | Likely Benign | 0.631 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -2.07 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1007 | 0.5877 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||
| c.3281C>T | S1094F 2D  AIThe SynGAP1 missense variant S1094F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -5.655 | Likely Benign | 0.666 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | -2.17 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.0925 | 0.5851 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3302C>A | P1101H 2D AIThe SynGAP1 missense variant P1101H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P1101H, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -5.370 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -1.87 | Neutral | 0.996 | Probably Damaging | 0.864 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 0.2046 | 0.4597 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3308G>C | R1103P 2D AIThe SynGAP1 missense variant R1103P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -2.149 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -2.48 | Neutral | 0.969 | Probably Damaging | 0.659 | Possibly Damaging | 2.43 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5109 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3308G>T | R1103L 2D  AIThe SynGAP1 missense variant R1103L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443860‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome (3 benign vs. 1 pathogenic votes). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443860-G-T | -2.330 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.35 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2098 | 0.5181 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.3313C>T | R1105W 2D  AIThe SynGAP1 missense variant R1105W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443865‑C‑T). Prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default tool remains uncertain. A consensus analysis (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1105W, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 1 | 6-33443865-C-T | 6 | 3.93e-6 | -6.911 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1154 | 0.4117 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3319C>G | Q1107E 2D  AIThe SynGAP1 missense variant Q1107E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.54 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.59 | Benign | 0.02 | Affected | 0.1453 | 0.2932 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.331C>A | P111T 2D AIThe SynGAP1 missense variant P111T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.800 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.44 | Neutral | 0.421 | Benign | 0.050 | Benign | 4.11 | Benign | 0.02 | Affected | 0.1650 | 0.5402 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3334G>A | E1112K 2D  AIThe SynGAP1 missense variant E1112K is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.772 | Likely Benign | 0.684 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | 0.15 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.82 | Benign | 0.02 | Affected | 0.3002 | 0.7704 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3335A>C | E1112A 2D  AIThe SynGAP1 missense variant E1112A is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (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, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.227 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -1.86 | Neutral | 0.393 | Benign | 0.131 | Benign | 2.71 | Benign | 0.02 | Affected | 0.3929 | 0.7528 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3341G>T | S1114I 2D AIThe SynGAP1 missense variant S1114I is reported in gnomAD (ID 6‑33443893‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443893-G-T | -6.718 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -1.86 | Neutral | 0.570 | Possibly Damaging | 0.292 | Benign | 2.65 | Benign | 0.02 | Affected | 4.32 | 2 | 0.1159 | 0.5276 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3355G>T | G1119W 2D AIThe SynGAP1 missense variant G1119W is reported in gnomAD (ID 6‑33443907‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443907-G-T | -10.904 | Likely Pathogenic | 0.336 | Likely Benign | Likely Benign | 0.386 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.949 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 4.32 | 2 | 0.0948 | 0.4059 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| c.3371G>A | G1124E 2D AIThe SynGAP1 missense variant G1124E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -10.403 | Likely Pathogenic | 0.345 | Ambiguous | Likely Benign | 0.301 | Likely Benign | -0.84 | Neutral | 0.126 | Benign | 0.066 | Benign | 4.78 | Benign | 0.02 | Affected | 0.1405 | 0.4063 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3371G>C | G1124A 2D AIThe SynGAP1 missense variant G1124A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and the Foldetta stability analysis is unavailable. Taken together, the overwhelming majority of computational evidence classifies G1124A as 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 | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -6.608 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -0.39 | Neutral | 0.059 | Benign | 0.041 | Benign | 4.81 | Benign | 0.02 | Affected | 0.3494 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3374G>T | G1125V 2D AIThe SynGAP1 missense variant G1125V is reported in gnomAD (variant ID 6-33443926-G-T) but has no ClinVar entry. Functional prediction tools cluster into two groups: six tools (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict a benign effect, whereas three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) 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 conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443926-G-T | -6.776 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.320 | Likely Benign | -0.99 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.55 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1407 | 0.3688 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3376G>T | G1126C 2D AIThe SynGAP1 missense variant G1126C is listed in ClinVar (ID 469157.0) with an “Uncertain” status and is present in gnomAD (6‑33443928‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | 6-33443928-G-T | 11 | 7.35e-6 | -9.389 | Likely Pathogenic | 0.113 | Likely Benign | Likely Benign | 0.449 | Likely Benign | -1.40 | Neutral | 0.005 | Benign | 0.005 | Benign | 4.74 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1326 | 0.4427 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||
| c.3377G>A | G1126D 2D AISynGAP1 missense variant G1126D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The AlphaMissense‑Default result is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign 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. | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | -8.888 | Likely Pathogenic | 0.432 | Ambiguous | Likely Benign | 0.376 | Likely Benign | -0.65 | Neutral | 0.906 | Possibly Damaging | 0.473 | Possibly Damaging | 4.82 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1725 | 0.2224 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3382G>T | G1128W 2D AIThe SynGAP1 missense variant G1128W is not 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), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields an inconclusive result (two benign, two uncertain), and Foldetta data are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -7.341 | In-Between | 0.402 | Ambiguous | Likely Benign | 0.464 | Likely Benign | -1.36 | Neutral | 0.011 | Benign | 0.008 | Benign | 4.36 | Benign | 0.02 | Affected | 0.0796 | 0.4540 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.3398T>A | I1133N 2D AIThe SynGAP1 missense variant I1133N is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for I1133N, 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 | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | -5.887 | Likely Benign | 0.520 | Ambiguous | Likely Benign | 0.290 | Likely Benign | -1.07 | Neutral | 0.453 | Possibly Damaging | 0.162 | Benign | 5.51 | Benign | 0.02 | Affected | 0.0961 | 0.1140 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3404A>T | K1135M 2D AIThe SynGAP1 K1135M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | -5.953 | Likely Benign | 0.931 | Likely Pathogenic | Ambiguous | 0.423 | Likely Benign | -1.65 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.1669 | 0.4164 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3433A>C | N1145H 2D AIThe SynGAP1 missense variant N1145H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the computational evidence supports a benign classification for the variant, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.974 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.391 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.41 | Benign | 0.02 | Affected | 0.1520 | 0.7233 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3439A>C | T1147P 2D AIThe SynGAP1 missense variant T1147P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -2.849 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.425 | Likely Benign | -2.17 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.41 | Benign | 0.02 | Affected | 0.1925 | 0.4490 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>A | T1147K 2D  AIThe SynGAP1 missense variant T1147K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of benign predictions and the lack of pathogenic evidence, T1147K 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 | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.921 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.386 | Likely Benign | -2.29 | Neutral | 0.126 | Benign | 0.096 | Benign | 5.50 | Benign | 0.02 | Affected | 0.1148 | 0.3200 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3454G>A | E1152K 2D AIThe SynGAP1 missense variant E1152K is reported in gnomAD (ID 6‑33444489‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus confirms a likely pathogenic outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which contains no classification for E1152K. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | 6-33444489-G-A | 1 | 6.20e-7 | -3.612 | Likely Benign | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | -2.64 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2942 | 0.6397 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.3455A>C | E1152A 2D AIThe SynGAP1 missense variant E1152A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence points to a pathogenic effect for E1152A. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -2.482 | Likely Benign | 0.927 | Likely Pathogenic | Ambiguous | 0.349 | Likely Benign | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.37 | Pathogenic | 0.02 | Affected | 0.4434 | 0.6557 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>A | V1155M 2D AISynGAP1 missense variant V1155M is not reported in ClinVar and is present in gnomAD (ID 6‑33444498‑G‑A). Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 slightly favors a benign interpretation, with no conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | 6-33444498-G-A | 1 | 6.20e-7 | -3.818 | Likely Benign | 0.915 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -1.19 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.57 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0779 | 0.4079 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||
| c.3464T>A | V1155E 2D  AIThe SynGAP1 missense variant V1155E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments highlight a discrepancy: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus indicates likely benign; Foldetta stability analysis is unavailable. Consequently, the evidence is evenly split between benign and pathogenic interpretations, and no ClinVar entry contradicts these findings. The variant’s clinical significance remains uncertain, with no definitive leaning toward benign or pathogenic based on current predictions. 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 | -3.175 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.204 | Likely Benign | -2.01 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.58 | Benign | 0.02 | Affected | 0.0973 | 0.1727 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3472G>T | V1158F 2D AIThe SynGAP1 missense variant V1158F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is classified as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. Foldetta results are unavailable. Overall, the majority of evidence indicates that V1158F is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.888 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.33 | Pathogenic | 0.02 | Affected | 0.0792 | 0.3577 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3473T>C | V1158A 2D AIThe SynGAP1 missense variant V1158A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence (six pathogenic vs. three benign predictions) indicates the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -2.726 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.232 | Likely Benign | -2.46 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.34 | Pathogenic | 0.02 | Affected | 0.2789 | 0.2906 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3478A>C | N1160H 2D AIThe SynGAP1 missense variant N1160H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. 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 (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.704 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.262 | Likely Benign | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.02 | Affected | 0.1152 | 0.6583 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3494C>G | S1165W 2D  AIThe SynGAP1 missense variant S1165W has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of tools supporting benign versus pathogenic effects. Consequently, the variant is most likely pathogenic based on the current computational 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 | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -6.419 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -2.29 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0671 | 0.4807 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3508A>T | S1170C 2D AIThe S1170C missense change occurs in a coiled‑coil region of SynGAP1. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized; those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), and SIFT. 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 and the SGM‑Consensus also as likely benign, while Foldetta results are unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, points to a benign impact for S1170C. This conclusion is not contradicted by ClinVar, which currently contains no classification for the variant. 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 | -6.393 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.566 | Likely Pathogenic | -2.07 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 5.30 | Benign | 0.02 | Affected | 0.0872 | 0.5850 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.350G>C | S117T 2D AIThe SynGAP1 missense variant S117T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, 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 SIFT predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this 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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.602 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.98 | Neutral | 0.608 | Possibly Damaging | 0.092 | Benign | 3.79 | Benign | 0.02 | Affected | 0.1527 | 0.5505 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3511_3512delinsTG | A1171C 2D  AIThe SynGAP1 missense variant A1171C (ClinVar ID 1723483.0) is listed as “Uncertain” in ClinVar and is not present in gnomAD. Prediction tools that converge on a benign outcome include PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which report a benign or neutral effect. In contrast, PolyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign,” reinforcing the benign signal. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | Uncertain | 1 | -5.363 | Likely Benign | 0.496 | Ambiguous | Likely Benign | -1.16 | Neutral | 0.978 | Probably Damaging | 0.825 | Possibly Damaging | 5.32 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1102 | 0.4921 | -2 | 0 | 0.7 | 32.06 | ||||||||||||||||||||||||||||||||||||
| c.3512C>A | A1171D 2D AIThe SynGAP1 missense variant A1171D is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” and Foldetta results are unavailable. Overall, the balance of evidence from multiple independent predictors and the SGM‑Consensus points to a benign impact for A1171D. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.897 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | -0.80 | Neutral | 0.611 | Possibly Damaging | 0.326 | Benign | 5.34 | Benign | 0.02 | Affected | 0.1952 | 0.2494 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||
| c.3515A>C | H1172P 2D AIThe SynGAP1 missense variant H1172P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign 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 predictor, has no available result for this variant. 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 | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.871 | Likely Benign | 0.653 | Likely Pathogenic | Likely Benign | 0.403 | Likely Benign | -2.09 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.2033 | 0.4128 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||
| c.3518T>A | I1173N 2D AIThe SynGAP1 missense variant I1173N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence points to a benign impact for I1173N, 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 | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -4.130 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.443 | Likely Benign | -1.46 | Neutral | 0.925 | Possibly Damaging | 0.611 | Possibly Damaging | 5.34 | Benign | 0.02 | Affected | 0.0920 | 0.0142 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3518T>G | I1173S 2D  AIThe SynGAP1 missense variant I1173S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for I1173S, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -2.416 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.455 | Likely Benign | -1.18 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 5.45 | Benign | 0.02 | Affected | 0.2796 | 0.0512 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3521A>C | E1174A 2D AIThe SynGAP1 missense variant E1174A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, 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 predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -3.512 | Likely Benign | 0.737 | Likely Pathogenic | Likely Benign | 0.413 | Likely Benign | -2.24 | Neutral | 0.790 | Possibly Damaging | 0.353 | Benign | 5.44 | Benign | 0.02 | Affected | 0.3462 | 0.5889 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.352A>G | M118V 2D  AIThe SynGAP1 missense variant M118V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -2.322 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -1.23 | Neutral | 0.012 | Benign | 0.011 | Benign | 3.98 | Benign | 0.02 | Affected | 0.3326 | 0.3630 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.3530A>G | E1177G 2D  AIThe SynGAP1 missense variant E1177G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.948 | Likely Benign | 0.727 | Likely Pathogenic | Likely Benign | 0.389 | Likely Benign | -2.04 | Neutral | 0.012 | Benign | 0.026 | Benign | 5.45 | Benign | 0.02 | Affected | 0.2690 | 0.4094 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.3533A>G | Y1178C 2D  AIThe SynGAP1 missense variant Y1178C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT, along with 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, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -4.581 | Likely Benign | 0.624 | Likely Pathogenic | Likely Benign | 0.353 | Likely Benign | -2.06 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 5.43 | Benign | 0.02 | Affected | 0.3439 | 0.1695 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||||||||
| c.3542A>C | K1181T 2D AIThe SynGAP1 missense variant K1181T is not reported in ClinVar and has no gnomAD allele. Prediction tools show a split: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the balance of evidence slightly favors pathogenicity, with no ClinVar entry to contradict this assessment. 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 | -4.378 | Likely Benign | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.30 | Neutral | 0.999 | Probably Damaging | 0.963 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.1655 | 0.3028 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.3543G>C | K1181N 2D AISynGAP1 missense variant K1181N is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 Pathogenic, whereas the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic effect, and this conclusion does not conflict with 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 | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | -4.872 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.111 | Likely Benign | -1.94 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.2812 | 0.1302 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3543G>T | K1181N 2D AIThe SynGAP1 missense variant K1181N is not reported in ClinVar and has no gnomAD entry. Prediction tools that classify it as benign include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all 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 pathogenic, whereas the SGM‑Consensus again indicates Likely Benign; Foldetta results are unavailable. Overall, the predictions are mixed, with a slight edge toward pathogenicity from individual tools but a consensus leaning benign. Therefore, the variant is most likely benign based on the collective evidence, and this assessment does not contradict ClinVar status, which currently has no classification for K1181N. 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 | -4.872 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.111 | Likely Benign | -1.94 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.2812 | 0.1302 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3544G>A | E1182K 2D AIThe SynGAP1 missense variant E1182K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.874 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.162 | Likely Benign | -2.04 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 0.02 | Affected | 0.1689 | 0.6152 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3544G>C | E1182Q 2D AIThe SynGAP1 missense variant E1182Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM‑Consensus remains likely benign, and Foldetta data are unavailable. Overall, the majority of evidence leans toward a benign effect, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.004 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.104 | Likely Benign | -1.43 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.02 | Affected | 0.0824 | 0.6009 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3545A>C | E1182A 2D AIThe SynGAP1 E1182A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, more tools predict pathogenicity (5) than benign (3), and the high‑accuracy methods do not overturn this trend. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.400 | Likely Benign | 0.888 | Likely Pathogenic | Ambiguous | 0.143 | Likely Benign | -2.73 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.3483 | 0.6025 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.354G>A | M118I 2D  AIThe SynGAP1 missense variant M118I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.396 | Likely Benign | 0.754 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.004 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1624 | 0.3570 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.354G>C | M118I 2D AIThe SynGAP1 missense variant M118I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.396 | Likely Benign | 0.754 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.004 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1624 | 0.3570 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.354G>T | M118I 2D AIThe SynGAP1 missense variant M118I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.396 | Likely Benign | 0.754 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.004 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1624 | 0.3570 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.355G>C | E119Q 2D AIThe SynGAP1 missense variant E119Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, SIFT, 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 therefore favor a benign effect: AlphaMissense‑Optimized is benign, and the SGM‑Consensus 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 that E119Q 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 | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -5.839 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | -1.38 | Neutral | 0.596 | Possibly Damaging | 0.143 | Benign | 3.84 | Benign | 0.02 | Affected | 0.1627 | 0.7886 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3560T>G | M1187R 2D AIThe SynGAP1 missense variant M1187R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as benign, and Foldetta results are unavailable. Overall, the majority of individual predictors (seven) indicate pathogenicity, whereas only three suggest benignity. Consequently, the variant is most likely pathogenic based on the available computational evidence, 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 | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -3.350 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.557 | Likely Pathogenic | -0.73 | Neutral | 0.968 | Probably Damaging | 0.978 | Probably Damaging | 5.52 | Benign | 0.02 | Affected | 0.1934 | 0.1000 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3566A>T | E1189V 2D AIThe SynGAP1 E1189V missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta stability predictions are not available. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy methods do not overturn this trend. 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. | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -5.048 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.492 | Likely Benign | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 5.26 | Benign | 0.02 | Affected | 0.0467 | 0.4252 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3571C>G | R1191G 2D AIThe SynGAP1 missense variant R1191G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate that R1191G is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | -3.142 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.304 | Likely Benign | -2.52 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.3728 | 0.3013 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3572G>C | R1191P 2D AIThe SynGAP1 missense variant R1191P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of evaluated tools (7 pathogenic vs 3 benign) indicate a pathogenic impact. This prediction 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. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | -2.355 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.320 | Likely Benign | -2.74 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.2253 | 0.4123 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3580A>G | R1194G 2D AIThe SynGAP1 missense variant R1194G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, and the high‑accuracy predictions are split, with no ClinVar evidence to contradict the pathogenic interpretation. 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. | Likely Benign | Coiled-coil | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | -6.849 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.477 | Likely Benign | -2.17 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.56 | Benign | 0.02 | Affected | 0.3275 | 0.2847 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3581G>C | R1194T 2D  AIThe SynGAP1 missense variant R1194T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with four tools supporting benign and four supporting pathogenic, and the high‑accuracy consensus is conflicting. Based on the available 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 | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | -4.875 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.402 | Likely Benign | -1.96 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.50 | Benign | 0.02 | Affected | 0.1866 | 0.3706 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||
| c.3582G>C | R1194S 2D AIThe SynGAP1 missense variant R1194S is not reported in ClinVar and is absent from gnomAD. Prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy analyses highlight AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta data are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, with a minority of tools and the consensus suggesting benignity. This prediction does not contradict ClinVar status, as no ClinVar entry exists for R1194S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | -5.139 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -1.60 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.57 | Benign | 0.02 | Affected | 0.3284 | 0.3281 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3582G>T | R1194S 2D AIThe SynGAP1 missense variant R1194S is not reported in ClinVar and is absent from gnomAD. Prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy analyses highlight AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta data are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, with a minority of tools and the consensus suggesting benignity. This prediction does not contradict ClinVar status, as no ClinVar entry exists for R1194S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | -5.139 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -1.60 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.57 | Benign | 0.02 | Affected | 0.3284 | 0.3281 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3584T>A | V1195E 2D AIThe SynGAP1 missense variant V1195E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 yields an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence leans toward a benign impact, with no conflict with ClinVar status (which has no entry). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -1.722 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.499 | Likely Benign | -2.19 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.64 | Benign | 0.02 | Affected | 0.0870 | 0.1268 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3599A>C | E1200A 2D AIThe SynGAP1 E1200A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy AlphaMissense‑Optimized score is benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (pathogenic), is benign. Foldetta results are unavailable. Overall, the balance of evidence (five benign versus four pathogenic predictions, with a benign SGM Consensus and high‑accuracy benign AlphaMissense‑Optimized) indicates that 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. | Coiled-coil | 0.545602 | Disordered | 0.458056 | Uncertain | 0.889 | 0.596 | 0.250 | -3.115 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.220 | Likely Benign | -2.61 | Deleterious | 0.994 | Probably Damaging | 0.926 | Probably Damaging | 2.72 | Benign | 0.02 | Affected | 0.2946 | 0.4513 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3601G>A | E1201K 2D AIThe SynGAP1 missense variant E1201K is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of computational evidence indicates that E1201K is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -10.090 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.437 | Likely Benign | -3.27 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.63 | Pathogenic | 0.02 | Affected | 0.1539 | 0.5812 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3602A>C | E1201A 2D AIThe SynGAP1 missense variant E1201A is not reported in ClinVar and has no entry in gnomAD. Consensus from in‑silico predictors shows a split: REVEL scores the change as benign, whereas all other tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, did not provide a result for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation, which is currently absent. 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 | -11.513 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.379 | Likely Benign | -4.68 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.62 | Pathogenic | 0.02 | Affected | 0.3191 | 0.5574 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3604A>T | I1202F 2D  AIThe SynGAP1 missense variant I1202F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) is likely pathogenic. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.510422 | Binding | 0.874 | 0.593 | 0.250 | -12.304 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -3.23 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.81 | Pathogenic | 0.02 | Affected | 0.0583 | 0.2079 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3616A>G | K1206E 2D AIThe SynGAP1 missense variant K1206E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and PROVEAN, whereas the majority of tools predict a pathogenic impact: polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for K1206E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -11.025 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.156 | Likely Benign | -1.87 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.44 | Pathogenic | 0.02 | Affected | 0.3247 | 0.1039 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3619G>A | E1207K 2D AIThe SynGAP1 missense variant E1207K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E1207K. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -8.145 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 0.261 | Likely Benign | -2.88 | Deleterious | 0.978 | Probably Damaging | 0.829 | Possibly Damaging | 2.12 | Pathogenic | 0.02 | Affected | 0.1796 | 0.4234 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3620A>C | E1207A 2D AIThe SynGAP1 missense variant E1207A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized indicates a benign effect, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a pathogenic effect for E1207A, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -8.277 | Likely Pathogenic | 0.679 | Likely Pathogenic | Likely Benign | 0.295 | Likely Benign | -4.27 | Deleterious | 0.989 | Probably Damaging | 0.829 | Possibly Damaging | 2.11 | Pathogenic | 0.02 | Affected | 0.3019 | 0.4305 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3623G>A | R1208Q 2D AIThe SynGAP1 missense variant R1208Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, and FATHMM, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie, and Foldetta data are unavailable. Overall, the majority of evidence points toward pathogenicity, 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. | Coiled-coil | 0.604312 | Disordered | 0.566942 | Binding | 0.899 | 0.569 | 0.375 | -8.434 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.14 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.2683 | 0.2040 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3628C>G | H1210D 2D  AIThe SynGAP1 missense variant H1210D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign impact, with no conflict with ClinVar status (which has no entry for this variant). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | -7.092 | In-Between | 0.530 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -2.98 | Deleterious | 0.680 | Possibly Damaging | 0.206 | Benign | 2.70 | Benign | 0.02 | Affected | 0.2051 | 0.1646 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3628C>T | H1210Y 2D AIThe SynGAP1 missense variant H1210Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign effect for H1210Y, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | -7.069 | In-Between | 0.145 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -1.93 | Neutral | 0.680 | Possibly Damaging | 0.206 | Benign | 2.68 | Benign | 0.02 | Affected | 0.0558 | 0.3384 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||||||
| c.362C>T | A121V 2D  AIThe SynGAP1 missense variant A121V is reported in gnomAD (ID 6‑33432227‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for A121V, 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 | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | 6-33432227-C-T | 3 | 1.86e-6 | -3.818 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -1.44 | Neutral | 0.213 | Benign | 0.050 | Benign | 4.04 | Benign | 0.02 | Affected | 3.61 | 5 | 0.1450 | 0.6898 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.3632T>C | M1211T 2D  AIThe SynGAP1 missense variant M1211T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -3.885 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.448 | Likely Benign | -1.99 | Neutral | 0.987 | Probably Damaging | 0.968 | Probably Damaging | 5.54 | Benign | 0.02 | Affected | 0.1987 | 0.1614 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||||||
| c.3637A>C | N1213H 2D AIThe SynGAP1 missense variant N1213H is predicted to be benign by the majority of in‑silico tools. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT classifies the change as pathogenic, while the consensus score from the SGM framework (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM Consensus also reports likely benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. The variant is not listed in ClinVar and has no entry in gnomAD, so there is no external evidence to contradict the computational predictions. Based on the collective predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | -5.358 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -1.23 | Neutral | 0.015 | Benign | 0.028 | Benign | 2.69 | Benign | 0.02 | Affected | 0.0883 | 0.4516 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||||
| c.3637A>T | N1213Y 2D AIThe SynGAP1 missense variant N1213Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic. AlphaMissense‑Optimized predicts benign, while high‑accuracy folding‑stability predictions from Foldetta are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and the consensus and high‑accuracy methods lean toward pathogenic. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | -8.972 | Likely Pathogenic | 0.483 | Ambiguous | Likely Benign | 0.083 | Likely Benign | -2.67 | Deleterious | 0.920 | Possibly Damaging | 0.657 | Possibly Damaging | 2.68 | Benign | 0.02 | Affected | 0.0439 | 0.3681 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3641G>A | R1214Q 2D AIThe SynGAP1 missense variant R1214Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446633‑G‑A). Functional prediction tools cluster into two groups: the benign‑predicating set includes REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the pathogenic‑predicating set consists of polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Taken together, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely benign, which is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | Uncertain | 1 | 6-33446633-G-A | 6 | 3.72e-6 | -6.059 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.69 | Neutral | 0.993 | Probably Damaging | 0.738 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 3.77 | 5 | 0.2162 | 0.1530 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||
| c.3643A>C | K1215Q 2D AIThe SynGAP1 missense variant K1215Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and PROVEAN, whereas the remaining tools—polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic impact for K1215Q, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.503613 | Binding | 0.888 | 0.568 | 0.375 | -9.763 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.099 | Likely Benign | -2.23 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.42 | Pathogenic | 0.02 | Affected | 0.4002 | 0.0856 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.367G>C | A123P 2D AIThe SynGAP1 missense variant A123P is listed in ClinVar (ID 4767034) with an “Uncertain” status and is not reported in gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, SIFT). 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 a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for A123P, and this conclusion does not contradict the current ClinVar designation of uncertainty. 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 | Uncertain | 1 | -2.930 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -1.14 | Neutral | 0.838 | Possibly Damaging | 0.278 | Benign | 4.14 | Benign | 0.02 | Affected | 0.2301 | 0.5999 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||
| c.3689C>A | T1230N 2D AIThe SynGAP1 missense variant T1230N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all 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 a benign likelihood. No Foldetta stability prediction is available for this variant. Overall, the majority of 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 | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -6.444 | Likely Benign | 0.613 | Likely Pathogenic | Likely Benign | 0.318 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.50 | Benign | 0.02 | Affected | 0.0799 | 0.2870 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||||||
| c.3689C>T | T1230I 2D  AIThe SynGAP1 missense variant T1230I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of evidence (seven pathogenic vs. three benign predictions) points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.661 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | -2.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.43 | Benign | 0.02 | Affected | 0.0581 | 0.4898 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.368C>T | A123V 2D AIThe SynGAP1 missense variant A123V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -4.119 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.77 | Neutral | 0.010 | Benign | 0.003 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1549 | 0.6874 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3703A>G | M1235V 2D AIThe SynGAP1 missense variant M1235V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. Only SIFT predicts a damaging effect. 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 benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this residue. Taken together, the preponderance of evidence indicates that M1235V 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 | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -3.870 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.54 | Neutral | 0.139 | Benign | 0.038 | Benign | 2.69 | Benign | 0.02 | Affected | 0.3048 | 0.3120 | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||||||
| c.3706C>A | Q1236K 2D  AIThe SynGAP1 missense variant Q1236K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence leans toward 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. | Coiled-coil | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -7.379 | In-Between | 0.512 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.64 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.73 | Benign | 0.02 | Affected | 0.1242 | 0.2503 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3712C>G | Q1238E 2D AIThe SynGAP1 missense variant Q1238E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized predicting benign, while SGM Consensus and Foldetta are unavailable. Overall, the majority of standard predictors (5 pathogenic vs 4 benign) lean toward a pathogenic interpretation, and this assessment does not contradict ClinVar status because no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | -10.421 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -1.90 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.37 | Pathogenic | 0.02 | Affected | 0.1078 | 0.1921 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3728A>G | Q1243R 2D  AIThe SynGAP1 missense variant Q1243R is catalogued in gnomAD (ID 6‑33446720‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | 6-33446720-A-G | 1 | 6.20e-7 | -7.131 | In-Between | 0.225 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -1.99 | Neutral | 0.912 | Possibly Damaging | 0.629 | Possibly Damaging | 2.67 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1181 | 0.1028 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||
| c.3728A>T | Q1243L 2D  AIThe SynGAP1 missense variant Q1243L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -6.092 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.168 | Likely Benign | -4.00 | Deleterious | 0.912 | Possibly Damaging | 0.629 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 0.0541 | 0.3364 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3729G>C | Q1243H 2D AIThe SynGAP1 missense variant Q1243H is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6-33446721‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | 6-33446721-G-C | 1 | 6.19e-7 | -5.281 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -1.90 | Neutral | 0.991 | Probably Damaging | 0.897 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0943 | 0.1813 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||
| c.3729G>T | Q1243H 2D AIThe SynGAP1 missense variant Q1243H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -5.281 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -1.90 | Neutral | 0.991 | Probably Damaging | 0.897 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0943 | 0.1813 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3731G>T | S1244I 2D AIThe SynGAP1 missense variant S1244I is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -13.073 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.284 | Likely Benign | -4.39 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.08 | Pathogenic | 0.02 | Affected | 0.0780 | 0.4684 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3737A>C | K1246T 2D AIThe SynGAP1 missense variant K1246T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification for K1246T, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -1.970 | Likely Benign | 0.263 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -2.19 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 0.2032 | 0.2065 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.3738G>C | K1246N 2D AIThe SynGAP1 missense variant K1246N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for K1246N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.506 | Likely Benign | 0.518 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -1.39 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | 0.3316 | 0.0940 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3738G>T | K1246N 2D AIThe SynGAP1 missense variant K1246N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for K1246N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.506 | Likely Benign | 0.518 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.39 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | 0.3316 | 0.0940 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.373C>G | P125A 2D AIThe SynGAP1 missense variant P125A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -3.936 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -3.55 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.88 | Benign | 0.02 | Affected | 0.3341 | 0.4245 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.373C>T | P125S 2D AIThe SynGAP1 missense variant P125S is listed in ClinVar (ID 837156.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | Uncertain | 1 | -3.769 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -3.57 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.86 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3408 | 0.4594 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3749A>C | Q1250P 2D AIThe SynGAP1 missense variant Q1250P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic. No Foldetta stability prediction is available for this variant. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -10.383 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.085 | Likely Benign | -3.12 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 2.62 | Benign | 0.02 | Affected | 0.2376 | 0.4149 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| c.3749A>T | Q1250L 2D AIThe SynGAP1 missense variant Q1250L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates “Likely Benign.” No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar, which contains no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.409 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -3.49 | Deleterious | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.0613 | 0.3946 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3750G>C | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for Q1250H, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3750G>T | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1250H, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3760G>A | E1254K 2D AIThe SynGAP1 missense variant E1254K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E1254K. This prediction is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -11.288 | Likely Pathogenic | 0.872 | Likely Pathogenic | Ambiguous | 0.290 | Likely Benign | -2.97 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.36 | Pathogenic | 0.02 | Affected | 0.1653 | 0.5488 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3761A>C | E1254A 2D AIThe SynGAP1 missense variant E1254A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining ten tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic 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 Pathogenic | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -8.943 | Likely Pathogenic | 0.658 | Likely Pathogenic | Likely Benign | 0.270 | Likely Benign | -4.35 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.35 | Pathogenic | 0.02 | Affected | 0.3029 | 0.5547 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3782G>T | S1261I 2D AIThe SynGAP1 missense variant S1261I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score indicates a benign effect, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. No Foldetta stability assessment is available for this residue. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic impact for S1261I. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -8.835 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.244 | Likely Benign | -4.20 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.02 | Affected | 0.0631 | 0.4410 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.380G>A | R127Q 2D AIThe SynGAP1 missense variant R127Q (ClinVar ID 2898917.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33432245‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar Uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | Uncertain | 1 | 6-33432245-G-A | 6 | 3.72e-6 | -1.711 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.04 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.04 | Benign | 0.02 | Affected | 3.74 | 4 | 0.3018 | 0.2852 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3856G>A | E1286K 2D AIThe SynGAP1 missense variant E1286K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447904‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs. 3 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet classified there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | 6-33447904-G-A | -3.784 | Likely Benign | 0.395 | Ambiguous | Likely Benign | 0.195 | Likely Benign | -2.36 | Neutral | 0.770 | Possibly Damaging | 0.242 | Benign | 2.47 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2069 | 0.5117 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||
| c.3857A>C | E1286A 2D AIThe SynGAP1 missense variant E1286A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.136 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -2.37 | Neutral | 0.770 | Possibly Damaging | 0.303 | Benign | 2.46 | Pathogenic | 0.02 | Affected | 0.3820 | 0.5016 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3860C>T | P1287L 2D AIThe SynGAP1 missense variant P1287L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33447908‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. 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 | Conflicting | 2 | 6-33447908-C-T | -2.800 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.66 | Neutral | 0.021 | Benign | 0.017 | Benign | 2.76 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1861 | 0.4727 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3866A>C | K1289T 2D AIThe SynGAP1 missense variant K1289T is not reported in ClinVar and is absent from gnomAD. Consensus prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this residue. Overall, the majority of computational evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.618 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.18 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.58 | Benign | 0.02 | Affected | 0.2047 | 0.2447 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3867G>C | K1289N 2D AIThe SynGAP1 missense variant K1289N is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, K1289N 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.244 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.043 | Likely Benign | -1.56 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.59 | Benign | 0.02 | Affected | 0.3442 | 0.0940 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3867G>T | K1289N 2D AIThe SynGAP1 missense variant K1289N is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, K1289N 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.244 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.043 | Likely Benign | -1.56 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.59 | Benign | 0.02 | Affected | 0.3442 | 0.0940 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>C | E1296A 2D AIThe SynGAP1 missense variant E1296A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are missing. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.562 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.238 | Likely Benign | -4.08 | Deleterious | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.61 | Benign | 0.02 | Affected | 0.3664 | 0.5506 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3890G>T | R1297M 2D  AIThe SynGAP1 missense variant R1297M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -4.286 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -3.00 | Deleterious | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.1294 | 0.2449 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.389A>T | Q130L 2D AIThe SynGAP1 missense variant Q130L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q130L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.643 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -1.63 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.11 | Benign | 0.02 | Affected | 0.0975 | 0.5286 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3907G>T | G1303C 2D AIThe SynGAP1 missense variant G1303C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -5.286 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.377 | Likely Benign | -2.49 | Neutral | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 2.76 | Benign | 0.02 | Affected | 0.1319 | 0.3681 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>T | G1303V 2D AIThe SynGAP1 missense variant G1303V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.513 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -2.44 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.79 | Benign | 0.02 | Affected | 0.1511 | 0.3508 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>T | T1305I 2D AIThe SynGAP1 missense variant T1305I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -4.202 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.35 | Neutral | 0.027 | Benign | 0.063 | Benign | 2.77 | Benign | 0.02 | Affected | 0.0923 | 0.6149 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.391G>A | G131S 2D AIThe SynGAP1 missense variant G131S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -2.953 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -2.75 | Deleterious | 0.115 | Benign | 0.026 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2823 | 0.5338 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3926T>C | V1309A 2D AIThe SynGAP1 missense variant V1309A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.336 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.269 | Likely Benign | -1.31 | Neutral | 0.088 | Benign | 0.085 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 0.2641 | 0.1797 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.392G>A | G131D 2D AIThe SynGAP1 missense variant G131D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools (ESM1b and AlphaMissense‑Optimized) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence (four pathogenic, three benign, two uncertain) leans toward pathogenicity. This prediction 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. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -7.477 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -3.29 | Deleterious | 0.888 | Possibly Damaging | 0.435 | Benign | 3.92 | Benign | 0.02 | Affected | 0.2093 | 0.2550 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3945G>C | W1315C 2D  AIThe SynGAP1 missense variant W1315C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT, together with 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, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | -2.355 | Likely Benign | 0.671 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -1.54 | Neutral | 0.872 | Possibly Damaging | 0.468 | Possibly Damaging | 4.21 | Benign | 0.02 | Affected | 0.3427 | 0.1929 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3945G>T | W1315C 2D AIThe SynGAP1 missense variant W1315C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for W1315C, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | -2.355 | Likely Benign | 0.671 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -1.54 | Neutral | 0.872 | Possibly Damaging | 0.468 | Possibly Damaging | 4.21 | Benign | 0.02 | Affected | 0.3427 | 0.1929 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3956C>T | A1319V 2D AIThe SynGAP1 missense variant A1319V is reported in gnomAD (ID 6‑33451830‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319V, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-T | 1 | 7.16e-7 | -5.015 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.17 | Neutral | 0.971 | Probably Damaging | 0.757 | Possibly Damaging | 4.14 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1583 | 0.6127 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.3989A>T | Q1330L 2D AIThe SynGAP1 missense variant Q1330L 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.780 | Likely Benign | 0.417 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -2.74 | Deleterious | 0.784 | Possibly Damaging | 0.341 | Benign | 3.92 | Benign | 0.02 | Affected | 0.0741 | 0.5480 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3990G>C | Q1330H 2D AIThe SynGAP1 missense variant Q1330H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus also reports it as likely benign, and Foldetta (which integrates FoldX‑MD and Rosetta stability calculations) has no available result for this residue. Based on the preponderance of benign predictions from multiple independent algorithms and the lack of pathogenic evidence, the variant is most likely benign. This conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.557 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.91 | Neutral | 0.969 | Probably Damaging | 0.732 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.1190 | 0.3996 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3990G>T | Q1330H 2D AIThe SynGAP1 missense variant Q1330H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus also reports it as likely benign, and Foldetta (which integrates FoldX‑MD and Rosetta stability calculations) has no available result for this residue. Based on the preponderance of benign predictions from multiple independent algorithms and the lack of pathogenic evidence, the variant is most likely benign. This conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.557 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.91 | Neutral | 0.969 | Probably Damaging | 0.732 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.1190 | 0.3996 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.4013G>A | R1338Q 2D AIThe SynGAP1 missense variant R1338Q is listed in ClinVar (ID 450879.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451887‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports it as “Likely Benign.” In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.977425 | Binding | 0.393 | 0.697 | 1.000 | Conflicting | 3 | 6-33451887-G-A | 12 | 8.40e-6 | -3.494 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.87 | Neutral | 0.896 | Possibly Damaging | 0.194 | Benign | 3.81 | Benign | 0.02 | Affected | 3.77 | 5 | 0.3528 | 0.2905 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.4018A>G | T1340A 2D AIThe SynGAP1 missense variant T1340A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, supports a benign classification. This prediction is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -3.192 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.01 | Neutral | 0.010 | Benign | 0.011 | Benign | 4.20 | Benign | 0.02 | Affected | 0.3984 | 0.4288 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.4019C>A | T1340N 2D AIThe SynGAP1 missense variant T1340N is reported in gnomAD (ID 6‑33451893‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T1340N. 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 | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451893-C-A | -3.664 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.95 | Neutral | 0.092 | Benign | 0.026 | Benign | 4.09 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1755 | 0.5309 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||||
| c.4021G>C | A1341P 2D AIThe SynGAP1 missense variant A1341P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | -3.168 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.59 | Neutral | 0.131 | Benign | 0.057 | Benign | 4.02 | Benign | 0.02 | Affected | 0.2154 | 0.5703 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.4022C>T | A1341V 2D AIThe SynGAP1 missense variant A1341V is catalogued in gnomAD (ID 6‑33451896‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for A1341V, 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 | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | 6-33451896-C-T | 1 | 6.29e-7 | -3.687 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.90 | Neutral | 0.006 | Benign | 0.011 | Benign | 4.04 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1398 | 0.6557 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.4024G>C | D1342H 2D AIThe SynGAP1 missense variant D1342H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of available predictions indicates that D1342H is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | -3.765 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.56 | Neutral | 0.834 | Possibly Damaging | 0.400 | Benign | 4.00 | Benign | 0.02 | Affected | 0.2365 | 0.6177 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.4025A>C | D1342A 2D AIThe SynGAP1 missense variant D1342A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. 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.” Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for D1342A, 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 | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | -2.719 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.58 | Neutral | 0.371 | Benign | 0.084 | Benign | 4.06 | Benign | 0.02 | Affected | 0.4270 | 0.5676 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.404G>A | R135Q 2D AIThe SynGAP1 missense variant R135Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33432701‑G‑A). Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. The remaining high‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie, and Foldetta stability analysis is not available. Overall, the balance of evidence favors a benign effect, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | Uncertain | 1 | 6-33432701-G-A | 5 | 3.84e-6 | -8.011 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.94 | Neutral | 0.327 | Benign | 0.100 | Benign | 3.76 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3153 | 0.2741 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||
| c.413A>G | K138R 2D  AIThe SynGAP1 missense variant K138R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact for K138R, and this conclusion does not conflict with the absence of a ClinVar assertion. 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 | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -5.135 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.115 | Likely Benign | -1.58 | Neutral | 0.247 | Benign | 0.163 | Benign | 3.66 | Benign | 0.02 | Affected | 0.4555 | 0.1036 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.439C>G | Q147E 2D AIThe SynGAP1 missense variant Q147E is not 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy AlphaMissense‑Optimized result is unavailable, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (2 pathogenic, 2 benign) and is therefore considered uncertain. Foldetta, which would assess protein‑folding stability, has no reported output for this variant, so its result is unavailable. Overall, the majority of evidence (five benign vs. three pathogenic) points to a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -10.347 | Likely Pathogenic | 0.840 | Likely Pathogenic | Ambiguous | 0.093 | Likely Benign | -1.47 | Neutral | 0.018 | Benign | 0.025 | Benign | 3.94 | Benign | 0.02 | Affected | 0.1561 | 0.1838 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.440A>G | Q147R 2D AIThe SynGAP1 missense variant Q147R is not reported 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, and FATHMM. Tools that agree on a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑to‑2 split, and Foldetta results are unavailable. Overall, more tools predict a benign outcome (five vs. three pathogenic predictions, with one uncertain). Therefore, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -12.301 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | -2.22 | Neutral | 0.079 | Benign | 0.052 | Benign | 3.91 | Benign | 0.02 | Affected | 0.1760 | 0.1042 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||||
| c.487T>G | F163V 2D AIThe SynGAP1 missense variant F163V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta data are not provided. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -12.580 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.236 | Likely Benign | -2.06 | Neutral | 0.981 | Probably Damaging | 0.954 | Probably Damaging | 4.13 | Benign | 0.02 | Affected | 0.2214 | 0.2547 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.496G>C | A166P 2D AIThe SynGAP1 missense variant A166P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for A166P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -9.665 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -2.04 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.99 | Benign | 0.02 | Affected | 0.1861 | 0.3668 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.497C>T | A166V 2D AIThe SynGAP1 missense variant A166V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.689 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -1.09 | Neutral | 0.141 | Benign | 0.091 | Benign | 4.07 | Benign | 0.02 | Affected | 0.1027 | 0.4281 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.503A>C | H168P 2D AIThe SynGAP1 missense variant H168P 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), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Taken together, the preponderance 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 | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -7.686 | In-Between | 0.124 | Likely Benign | Likely Benign | 0.279 | Likely Benign | -1.66 | Neutral | 0.072 | Benign | 0.043 | Benign | 4.19 | Benign | 0.02 | Affected | 0.2004 | 0.3960 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.503A>G | H168R 2D AIThe SynGAP1 missense variant H168R is reported in gnomAD (ID 6‑33432800‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all classify the change as benign, whereas SIFT predicts it to be pathogenic. Two tools (ESM1b and AlphaMissense‑Default) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are not available. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | 6-33432800-A-G | 1 | 6.20e-7 | -7.334 | In-Between | 0.395 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -1.08 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.26 | Benign | 0.02 | Affected | 4.32 | 3 | 0.1752 | 0.2499 | 0 | 2 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||
| c.504T>A | H168Q 2D AIThe SynGAP1 missense variant H168Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -5.177 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.85 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.31 | Benign | 0.02 | Affected | 0.1307 | 0.3873 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.504T>G | H168Q 2D AIThe SynGAP1 missense variant H168Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -5.177 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.85 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.31 | Benign | 0.02 | Affected | 0.1307 | 0.3873 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.511G>C | A171P 2D AIThe SynGAP1 missense variant A171P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta results are unavailable for this variant. Overall, the majority of computational 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 | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -5.071 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | -1.42 | Neutral | 0.396 | Benign | 0.099 | Benign | 4.14 | Benign | 0.02 | Affected | 0.1630 | 0.3938 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.514C>G | R172G 2D AIThe SynGAP1 R172G missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Computational predictions are split: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy consensus tools are inconclusive: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Consequently, the variant is neither clearly benign nor pathogenic according to current predictions, and there is no ClinVar annotation to contradict this ambiguous assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | -6.685 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -2.69 | Deleterious | 0.789 | Possibly Damaging | 0.253 | Benign | 3.98 | Benign | 0.02 | Affected | 0.2991 | 0.3169 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.515G>T | R172L 2D AIThe SynGAP1 missense variant R172L is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the majority of evidence, including the SGM Consensus, points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | -8.201 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.131 | Likely Benign | -3.09 | Deleterious | 0.276 | Benign | 0.103 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1423 | 0.4729 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.526A>T | S176C 2D AIThe SynGAP1 missense variant S176C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy tools indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -9.785 | Likely Pathogenic | 0.529 | Ambiguous | Likely Benign | 0.143 | Likely Benign | -1.88 | Neutral | 0.983 | Probably Damaging | 0.436 | Benign | 4.02 | Benign | 0.02 | Affected | 0.0823 | 0.5153 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.535G>A | E179K 2D AIThe SynGAP1 missense variant E179K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (five pathogenic vs. four benign) indicate a pathogenic impact. No ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -11.305 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.174 | Likely Benign | -2.32 | Neutral | 0.596 | Possibly Damaging | 0.202 | Benign | 4.03 | Benign | 0.02 | Affected | 0.2867 | 0.7695 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.535G>C | E179Q 2D AIThe SynGAP1 missense variant E179Q has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Computational predictions are split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy consensus tools are inconclusive: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a tie, and Foldetta results are unavailable. Consequently, the variant is neither clearly benign nor pathogenic based on current predictions, and there is no ClinVar status to contradict this ambiguous assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -10.388 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | -1.82 | Neutral | 0.818 | Possibly Damaging | 0.419 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1674 | 0.7383 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.538T>A | S180T 2D AIThe SynGAP1 missense variant S180T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -9.851 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -2.07 | Neutral | 0.057 | Benign | 0.020 | Benign | 3.86 | Benign | 0.02 | Affected | 0.1238 | 0.5171 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.541C>G | H181D 2D AIThe SynGAP1 missense variant H181D has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: the SGM‑Consensus is pathogenic, AlphaMissense‑Optimized remains uncertain, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact. Because there is no ClinVar classification to oppose this, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -15.380 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | -2.93 | Deleterious | 0.596 | Possibly Damaging | 0.107 | Benign | 4.17 | Benign | 0.02 | Affected | 0.2157 | 0.1255 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.541C>T | H181Y 2D AIThe SynGAP1 missense variant H181Y is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33435183‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H181Y, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | 6-33435183-C-T | 2 | 1.24e-6 | -9.477 | Likely Pathogenic | 0.551 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.36 | Neutral | 0.818 | Possibly Damaging | 0.255 | Benign | 4.13 | Benign | 0.02 | Affected | 3.54 | 6 | 0.0588 | 0.3875 | 2 | 0 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.559C>A | L187M 2D AIThe SynGAP1 missense variant L187M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, which would assess protein‑folding stability, has no available output for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -8.814 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -1.35 | Neutral | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 3.72 | Benign | 0.02 | Affected | 0.0848 | 0.3613 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.559C>G | L187V 2D  AIThe SynGAP1 missense variant L187V is not 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard predictors lean toward a benign classification, but the single high‑accuracy tool indicates pathogenicity. Thus, the variant is most likely benign based on the collective evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -10.543 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.136 | Likely Benign | -2.24 | Neutral | 0.437 | Benign | 0.079 | Benign | 3.81 | Benign | 0.02 | Affected | 0.1525 | 0.3509 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.574G>C | A192P 2D AIThe SynGAP1 missense variant A192P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools points to a pathogenic 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 Pathogenic | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -9.795 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.245 | Likely Benign | -3.35 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.1658 | 0.3719 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.575C>G | A192G 2D  AIThe SynGAP1 missense variant A192G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -9.003 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | -3.00 | Deleterious | 0.989 | Probably Damaging | 0.621 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.2081 | 0.2857 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.580G>C | E194Q 2D AIThe SynGAP1 missense variant E194Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, more evidence supports a pathogenic classification (5 pathogenic vs. 3 benign predictions). Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -8.902 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -1.97 | Neutral | 0.849 | Possibly Damaging | 0.478 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 0.1043 | 0.4954 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.584C>A | A195E 2D  AIThe SynGAP1 missense variant A195E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -10.909 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.237 | Likely Benign | -3.20 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0855 | 0.1877 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.589G>A | E197K 2D AIThe SynGAP1 missense variant E197K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. Grouping by consensus, the majority of high‑confidence predictors (AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, SIFT, ESM1b) indicate pathogenicity, while a minority (REVEL, polyPhen‑2, FATHMM) suggest benign impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, is classified as Likely Pathogenic. AlphaMissense‑Optimized also predicts Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E197K, and this assessment does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -11.045 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -2.50 | Deleterious | 0.118 | Benign | 0.037 | Benign | 4.09 | Benign | 0.02 | Affected | 0.1824 | 0.5890 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.589G>C | E197Q 2D AIThe SynGAP1 E197Q variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT 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 also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -6.347 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | -1.75 | Neutral | 0.396 | Benign | 0.067 | Benign | 4.05 | Benign | 0.02 | Affected | 0.0867 | 0.5228 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.590A>C | E197A 2D AIThe SynGAP1 E197A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta (which would combine FoldX‑MD and Rosetta outputs) has no available result. Overall, the balance of evidence—including the pathogenic majority in the high‑accuracy consensus—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -7.956 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -3.56 | Deleterious | 0.055 | Benign | 0.016 | Benign | 4.06 | Benign | 0.02 | Affected | 0.3134 | 0.5290 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.599T>G | L200W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact. Two tools (AlphaMissense‑Optimized and Rosetta) provide inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Pathogenic, the latter integrating stability predictions from FoldX‑MD and Rosetta. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -11.550 | Likely Pathogenic | 0.824 | Likely Pathogenic | Ambiguous | 2.90 | Destabilizing | 1.0 | 1.95 | Ambiguous | 2.43 | Destabilizing | 1.20 | Destabilizing | 0.200 | Likely Benign | -2.93 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 3.98 | Benign | 0.02 | Affected | 0.0627 | 0.2893 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.601G>T | D201Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D201Y missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Rosetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus predicts likely pathogenic; Foldetta is uncertain. Because the majority of consensus and individual predictors (seven pathogenic vs four benign) lean toward a damaging outcome, the variant is most likely pathogenic. This assessment is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.916 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.28 | Likely Benign | 0.2 | 2.39 | Destabilizing | 1.34 | Ambiguous | 0.31 | Likely Benign | 0.334 | Likely Benign | -4.93 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.02 | Benign | 0.02 | Affected | 0.0431 | 0.5371 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.602A>T | D201V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. With the majority of tools indicating pathogenicity and no ClinVar record to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.283 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.87 | Ambiguous | 0.1 | 2.18 | Destabilizing | 1.53 | Ambiguous | 0.31 | Likely Benign | 0.305 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.02 | Affected | 0.0572 | 0.5207 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.604G>C | E202Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -7.129 | In-Between | 0.456 | Ambiguous | Likely Benign | -0.16 | Likely Benign | 0.0 | 0.23 | Likely Benign | 0.04 | Likely Benign | -0.13 | Likely Benign | 0.175 | Likely Benign | -1.39 | Neutral | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 4.07 | Benign | 0.02 | Affected | 0.0949 | 0.6792 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.605A>C | E202A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools (AlphaMissense‑Default and ESM1b) 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) is inconclusive and therefore 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. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -7.222 | In-Between | 0.538 | Ambiguous | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.14 | Likely Benign | 0.14 | Likely Benign | 0.19 | Likely Benign | 0.220 | Likely Benign | -4.05 | Deleterious | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 4.02 | Benign | 0.02 | Affected | 0.3903 | 0.6468 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.607G>C | D203H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or folding result is missing or inconclusive. Overall, the predictions are mixed, but the two high‑accuracy tools favor a benign outcome, giving a slight bias toward benign. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -9.130 | Likely Pathogenic | 0.593 | Likely Pathogenic | Likely Benign | 0.00 | Likely Benign | 0.1 | 0.18 | Likely Benign | 0.09 | Likely Benign | -0.04 | Likely Benign | 0.218 | Likely Benign | -3.28 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 3.98 | Benign | 0.02 | Affected | 0.0962 | 0.4815 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.608A>T | D203V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools and the SGM Consensus lean toward a pathogenic interpretation, whereas two high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest benign. Because ClinVar contains no entry for this variant, there is no contradiction between the predictions and existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -10.660 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.32 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.38 | Likely Benign | 0.05 | Likely Benign | 0.289 | Likely Benign | -4.07 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 3.98 | Benign | 0.02 | Affected | 0.0534 | 0.4084 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||
| c.622C>T | P208S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Rosetta’s output is uncertain and therefore not counted as evidence. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic, and Foldetta also predicts pathogenic. With no ClinVar annotation to contradict, the overall evidence strongly favors a pathogenic classification for P208S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -8.363 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | 2.68 | Destabilizing | 0.3 | 1.53 | Ambiguous | 2.11 | Destabilizing | 1.21 | Destabilizing | 0.270 | Likely Benign | -6.78 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.79 | Benign | 0.02 | Affected | 0.3808 | 0.4537 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.625G>A | V209M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V209M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -8.112 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.70 | Ambiguous | 0.4 | 0.77 | Ambiguous | 0.74 | Ambiguous | 0.78 | Ambiguous | 0.115 | Likely Benign | -1.48 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 3.68 | Benign | 0.02 | Affected | 0.0669 | 0.3982 | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||
| c.626T>C | V209A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209A is reported in gnomAD (ID 6‑33435268‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL and FATHMM. In contrast, a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, and the combined Foldetta score are uncertain and therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that V209A is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | 6-33435268-T-C | 1 | 6.20e-7 | -9.796 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.3 | 1.85 | Ambiguous | 1.71 | Ambiguous | 1.60 | Destabilizing | 0.236 | Likely Benign | -2.79 | Deleterious | 0.958 | Probably Damaging | 0.581 | Possibly Damaging | 3.70 | Benign | 0.02 | Affected | 3.41 | 13 | 0.2237 | 0.1919 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||
| c.631A>C | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a pathogenic signal is reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools predict a pathogenic effect, and the high‑accuracy predictions reinforce this conclusion. The variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.132 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.633C>A | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, FATHMM, and Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions and the two high‑accuracy pathogenic calls suggest that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.144 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.633C>G | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, FATHMM, and the protein‑stability integrator Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and premPS is uncertain. High‑accuracy assessments give conflicting signals: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, but Foldetta, which combines FoldX‑MD and Rosetta outputs, predicts Benign. Overall, the majority of tools and the consensus score point to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.144 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.643G>A | G215S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining pathogenic predictors (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all indicate pathogenicity. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -9.067 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.30 | Destabilizing | 0.3 | 1.20 | Ambiguous | 1.75 | Ambiguous | 0.55 | Ambiguous | 0.864 | Likely Pathogenic | -5.05 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.66 | Benign | 0.02 | Affected | 0.2701 | 0.5761 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.644G>A | G215D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SIFT, PolyPhen‑2 (HumDiv and HumVar), PROVEAN, REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and FoldX—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which evaluates protein‑folding stability, yields an uncertain result. No other high‑confidence tool contradicts the pathogenic prediction. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -9.884 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.23 | Destabilizing | 0.3 | 0.91 | Ambiguous | 1.57 | Ambiguous | 0.57 | Ambiguous | 0.807 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.71 | Benign | 0.02 | Affected | 0.1888 | 0.2947 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.644G>C | G215A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tool predicting a benign outcome is FATHMM. Predictions that are uncertain or inconclusive are Foldetta, Rosetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta is uncertain. Overall, the majority of evidence indicates that G215A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -8.930 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.36 | Destabilizing | 0.2 | 1.35 | Ambiguous | 1.86 | Ambiguous | 0.59 | Ambiguous | 0.874 | Likely Pathogenic | -5.08 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.61 | Benign | 0.02 | Affected | 0.3897 | 0.5525 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.655T>G | C219G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 11 tools—including REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect for C219G. This conclusion aligns with the absence of a ClinVar entry and does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.072 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.3 | 1.98 | Ambiguous | 1.35 | Ambiguous | 1.18 | Destabilizing | 0.900 | Likely Pathogenic | -10.09 | Deleterious | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.02 | Affected | 0.2159 | 0.2169 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.658T>C | F220L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic 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 Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | 0.850 | Likely Pathogenic | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 0.2589 | 0.4108 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.660T>A | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic 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 Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | 0.752 | Likely Pathogenic | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 0.2589 | 0.4108 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.660T>G | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic 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 Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | 0.752 | Likely Pathogenic | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 0.2589 | 0.4108 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.661G>A | E221K 2D AIThe SynGAP1 E221K 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 Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. FoldX and Foldetta give uncertain results. High‑accuracy methods show AlphaMissense‑Optimized as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of reliable predictors indicate 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. | Likely Pathogenic | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.331 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.01 | Ambiguous | 0.4 | -0.18 | Likely Benign | -0.60 | Ambiguous | 0.19 | Likely Benign | 0.815 | Likely Pathogenic | -2.92 | Deleterious | 0.131 | Benign | 0.058 | Benign | 5.92 | Benign | 0.02 | Affected | 0.2491 | 0.8002 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.663G>C | E221D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta remains uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.237 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.59 | Ambiguous | 0.1 | 1.07 | Ambiguous | 1.33 | Ambiguous | 0.84 | Ambiguous | 0.750 | Likely Pathogenic | -2.43 | Neutral | 0.421 | Benign | 0.107 | Benign | 5.80 | Benign | 0.02 | Affected | 0.1755 | 0.5228 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.663G>T | E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.237 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.59 | Ambiguous | 0.1 | 1.07 | Ambiguous | 1.33 | Ambiguous | 0.84 | Ambiguous | 0.750 | Likely Pathogenic | -2.43 | Neutral | 0.421 | Benign | 0.107 | Benign | 5.80 | Benign | 0.02 | Affected | 0.1755 | 0.5228 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.667A>T | T223S 2D  3DClick to see structure in 3D Viewer AISynGAP1 T223S is listed in ClinVar as a variant of uncertain significance and is present in the gnomAD database (ID 6‑33435518‑A‑T). Functional prediction tools that reach consensus classify the variant as benign: FoldX, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity include REVEL, PROVEAN, and SIFT. Predictions that are inconclusive or uncertain are Rosetta, premPS, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic calls. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | Conflicting | 2 | 6-33435518-A-T | 3 | 1.86e-6 | -7.714 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.26 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.38 | Likely Benign | 0.62 | Ambiguous | 0.535 | Likely Pathogenic | -2.86 | Deleterious | 0.421 | Benign | 0.058 | Benign | 5.80 | Benign | 0.02 | Affected | 3.41 | 13 | 0.2388 | 0.2972 | 1 | 1 | -0.1 | -14.03 | 200.7 | 17.3 | -0.2 | 0.2 | 0.0 | 0.0 | X | Uncertain | The introduced residue Ser223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Its hydroxyl group forms hydrogen bonds with nearby residues Thr228 and Lys207 in the variant simulations, similar to the hydroxyl group of Thr223 in the WT simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and may prevent it from unfolding. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||
| c.682A>C | T228P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is inconclusive, but the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.559 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.6 | 0.47 | Likely Benign | 1.06 | Ambiguous | 0.21 | Likely Benign | 0.690 | Likely Pathogenic | -3.54 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.64 | Benign | 0.02 | Affected | 0.2207 | 0.6360 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.683C>A | T228K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results (Rosetta and premPS). High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any existing ClinVar annotation because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -9.143 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.03 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.45 | Likely Benign | 0.70 | Ambiguous | 0.676 | Likely Pathogenic | -3.00 | Deleterious | 0.906 | Possibly Damaging | 0.521 | Possibly Damaging | 5.60 | Benign | 0.02 | Affected | 0.1322 | 0.3590 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.685A>C | K229Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, FATHMM, and Foldetta; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not conflict with ClinVar status, which currently has no entry for K229Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -9.606 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.41 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.18 | Likely Benign | 0.55 | Ambiguous | 0.813 | Likely Pathogenic | -3.03 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.4456 | 0.1057 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.695C>A | A232D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Uncertain or inconclusive results are reported for Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as pathogenic, while Foldetta remains uncertain. Overall, the majority of available predictions support a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -13.956 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.14 | Likely Benign | 0.2 | 1.55 | Ambiguous | 0.85 | Ambiguous | 0.77 | Ambiguous | 0.725 | Likely Pathogenic | -2.50 | Deleterious | 0.845 | Possibly Damaging | 0.348 | Benign | 5.78 | Benign | 0.02 | Affected | 0.2066 | 0.2896 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.707C>A | A236E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236E is not reported in ClinVar and is present in gnomAD (ID 6‑33435558‑C‑A). Functional prediction tools show a split assessment: benign calls come from FATHMM, Rosetta, and the protein‑folding stability method Foldetta; pathogenic calls come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. When grouped by agreement, the benign‑predicting tools (FATHMM, Rosetta, Foldetta) represent one consensus, while the pathogenic‑predicting tools (REVEL, premPS, PROVEAN, polyPhen‑2, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus) form the opposing consensus. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | 6-33435558-C-A | 1 | 6.20e-7 | -10.844 | Likely Pathogenic | 0.835 | Likely Pathogenic | Ambiguous | -0.75 | Ambiguous | 0.2 | 0.28 | Likely Benign | -0.24 | Likely Benign | 1.08 | Destabilizing | 0.844 | Likely Pathogenic | -4.24 | Deleterious | 0.998 | Probably Damaging | 0.900 | Possibly Damaging | 6.06 | Benign | 0.02 | Affected | 3.40 | 14 | 0.1075 | 0.1970 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||
| c.715A>G | R239G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239G 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 are limited to FATHMM, whereas the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -12.133 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.05 | Destabilizing | 0.1 | 3.41 | Destabilizing | 3.73 | Destabilizing | 1.33 | Destabilizing | 0.912 | Likely Pathogenic | -6.26 | Deleterious | 0.982 | Probably Damaging | 0.533 | Possibly Damaging | 5.62 | Benign | 0.02 | Affected | 0.3415 | 0.3154 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.717A>C | R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | 0.813 | Likely Pathogenic | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0.3160 | 0.3788 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.717A>T | R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | 0.813 | Likely Pathogenic | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0.3160 | 0.3788 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.727A>T | I243F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 3 benign) indicate a likely pathogenic impact. This assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -12.559 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 2.92 | Destabilizing | 2.5 | 0.53 | Ambiguous | 1.73 | Ambiguous | 0.42 | Likely Benign | 0.793 | Likely Pathogenic | -2.21 | Neutral | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.53 | Benign | 0.02 | Affected | 0.0409 | 0.2205 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||
| c.740A>C | Q247P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; premPS is uncertain and therefore treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -14.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.43 | Destabilizing | 0.2 | 7.83 | Destabilizing | 5.63 | Destabilizing | 0.81 | Ambiguous | 0.770 | Likely Pathogenic | -3.56 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.69 | Benign | 0.02 | Affected | 0.1768 | 0.3631 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.740A>T | Q247L 2D AIThe SynGAP1 missense variant Q247L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence (seven pathogenic versus three benign predictions) points to a pathogenic impact, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -10.554 | Likely Pathogenic | 0.352 | Ambiguous | Likely Benign | -0.86 | Ambiguous | 0.5 | -1.14 | Ambiguous | -1.00 | Ambiguous | 0.38 | Likely Benign | 0.687 | Likely Pathogenic | -3.89 | Deleterious | 0.982 | Probably Damaging | 0.628 | Possibly Damaging | 5.70 | Benign | 0.02 | Affected | 0.0573 | 0.4129 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.741G>C | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SGM‑Consensus, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Tools that predict a pathogenic outcome are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.741G>T | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Those that predict a pathogenic impact are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall balance of evidence—seven benign versus five pathogenic predictions, and all high‑accuracy tools indicating benign—the variant is most likely benign. This conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.749T>C | V250A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250A missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all indicate pathogenicity, whereas ESM1b and FATHMM predict a benign outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is balanced and therefore unavailable, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V250A, and this assessment does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.385 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.82 | Ambiguous | 0.1 | 1.22 | Ambiguous | 1.02 | Ambiguous | 1.48 | Destabilizing | 0.818 | Likely Pathogenic | -3.11 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 5.82 | Benign | 0.02 | Affected | 0.2491 | 0.2151 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.767A>G | N256S 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256S is listed in ClinVar as Pathogenic (ClinVar ID 2584352.0) and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy subset gives AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions support a pathogenic effect, aligning with the ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | Likely Pathogenic | 1 | -10.640 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 0.2 | 0.36 | Likely Benign | 0.34 | Likely Benign | 0.48 | Likely Benign | 0.707 | Likely Pathogenic | -4.33 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.02 | Affected | 3.39 | 15 | 0.3024 | 0.5864 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.781G>A | D261N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261N is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS, FATHMM, and AlphaMissense‑Optimized, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -11.804 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 1.58 | Ambiguous | 0.7 | 1.28 | Ambiguous | 1.43 | Ambiguous | 0.23 | Likely Benign | 0.579 | Likely Pathogenic | -2.94 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.82 | Benign | 0.02 | Affected | 0.0767 | 0.4745 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.782A>G | D261G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -10.847 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 2.81 | Destabilizing | 0.5 | 2.96 | Destabilizing | 2.89 | Destabilizing | 0.21 | Likely Benign | 0.850 | Likely Pathogenic | -4.77 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.81 | Benign | 0.02 | Affected | 0.2924 | 0.4562 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.786T>A | N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact for N262K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -12.512 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.74 | Ambiguous | 0.33 | Likely Benign | 0.531 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.1799 | 0.3413 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.786T>G | N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree: benign predictions come from FoldX, premPS, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Taken together, the majority of evidence points to a pathogenic effect for N262K. This conclusion is consistent with the absence of a ClinVar classification, as there is no existing report to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -12.512 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.74 | Ambiguous | 0.33 | Likely Benign | 0.532 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.1799 | 0.3413 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.790C>A | L264I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L264I is not reported in ClinVar and is present in gnomAD (ID 6‑33437695‑C‑A). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the balance of evidence—six pathogenic versus three benign predictions, a pathogenic SGM Consensus, and an uncertain Foldetta—suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | 6-33437695-C-A | 1 | 6.20e-7 | -10.945 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 1.90 | Ambiguous | 0.5 | 0.84 | Ambiguous | 1.37 | Ambiguous | 0.95 | Ambiguous | 0.418 | Likely Benign | -1.84 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 0.66 | Pathogenic | 0.02 | Affected | 3.38 | 18 | 0.0764 | 0.2630 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||
| c.810G>C | E270D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Rosetta. Tools with inconclusive results—FoldX, Foldetta, and premPS—are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -11.954 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.1 | 2.15 | Destabilizing | 1.84 | Ambiguous | 0.91 | Ambiguous | 0.379 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.60 | Pathogenic | 0.02 | Affected | 0.1908 | 0.2540 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.810G>T | E270D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, and the SGM‑Consensus (which is “Likely Pathogenic”). Predictions that are inconclusive or uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicating a likely pathogenic outcome, while Foldetta’s stability analysis is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E270D, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -11.954 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.1 | 2.15 | Destabilizing | 1.84 | Ambiguous | 0.91 | Ambiguous | 0.383 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.60 | Pathogenic | 0.02 | Affected | 0.1908 | 0.2540 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.812C>T | A271V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, and Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -8.185 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | -0.22 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.28 | Likely Benign | 0.37 | Likely Benign | 0.466 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.69 | Pathogenic | 0.02 | Affected | 0.0986 | 0.4409 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.820C>G | L274V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while both the SGM‑Consensus and Foldetta (combining FoldX‑MD and Rosetta outputs) predict pathogenicity. No predictions are missing or inconclusive. Overall, the preponderance of evidence from multiple independent tools points to a pathogenic impact for L274V. 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 Pathogenic | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | -5.634 | Likely Benign | 0.593 | Likely Pathogenic | Likely Benign | 2.13 | Destabilizing | 0.6 | 2.22 | Destabilizing | 2.18 | Destabilizing | 0.99 | Ambiguous | 0.378 | Likely Benign | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 0.10 | Pathogenic | 0.02 | Affected | 0.1448 | 0.1860 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.829A>C | K277Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K277Q is reported in gnomAD (ID 6‑33437734‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from FoldX, Foldetta, and premPS; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | 6-33437734-A-C | 1 | 6.20e-7 | -12.547 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.33 | Likely Benign | 0.42 | Likely Benign | 0.655 | Likely Pathogenic | -3.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 0.4000 | 0.0672 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||
| c.835C>G | R279G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279G 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 only REVEL, which scores the variant as benign. All other evaluated tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote) which labels it “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus remains “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | -9.941 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 3.10 | Destabilizing | 0.7 | 2.85 | Destabilizing | 2.98 | Destabilizing | 1.11 | Destabilizing | 0.442 | Likely Benign | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.2961 | 0.2209 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.836G>C | R279P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign effect. FoldX reports an uncertain outcome, but Rosetta, Foldetta, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, based on a majority vote of the aforementioned predictors, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | -14.926 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.42 | Ambiguous | 0.9 | 4.27 | Destabilizing | 2.85 | Destabilizing | 1.21 | Destabilizing | 0.626 | Likely Pathogenic | -5.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2179 | 0.3281 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.838T>G | Y280D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -16.885 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.2 | 5.89 | Destabilizing | 5.90 | Destabilizing | 2.00 | Destabilizing | 0.580 | Likely Pathogenic | -9.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 0.3593 | 0.0212 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.839A>T | Y280F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—premPS, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of available predictions favor a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -7.844 | In-Between | 0.414 | Ambiguous | Likely Benign | 0.49 | Likely Benign | 0.2 | 0.03 | Likely Benign | 0.26 | Likely Benign | 0.87 | Ambiguous | 0.544 | Likely Pathogenic | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.98 | Pathogenic | 0.02 | Affected | 0.2263 | 0.2398 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.856C>A | L286M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (premPS 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 predictions (seven pathogenic vs. five benign) and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.122885 | Structured | 0.385647 | Uncertain | 0.932 | 0.260 | 0.000 | -7.998 | In-Between | 0.781 | Likely Pathogenic | Likely Benign | -0.06 | Likely Benign | 0.1 | 0.17 | Likely Benign | 0.06 | Likely Benign | 0.98 | Ambiguous | 0.663 | Likely Pathogenic | -1.84 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.54 | Pathogenic | 0.02 | Affected | 0.0789 | 0.3371 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.868C>A | L290M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, and PROVEAN, whereas pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain outcomes include Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy analyses indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence leans toward a pathogenic 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 Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -8.393 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.2 | 0.98 | Ambiguous | 0.73 | Ambiguous | 0.59 | Ambiguous | 0.438 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.0823 | 0.4167 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.871T>C | Y291H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291H is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic verdict; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -8.749 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.13 | Destabilizing | 0.2 | 2.61 | Destabilizing | 2.37 | Destabilizing | 1.56 | Destabilizing | 0.355 | Likely Benign | -4.04 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.77 | Pathogenic | 0.02 | Affected | 0.2403 | 0.0499 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.872A>C | Y291S 2D  AIThe SynGAP1 missense variant Y291S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -11.928 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 0.8 | 4.47 | Destabilizing | 3.97 | Destabilizing | 2.01 | Destabilizing | 0.588 | Likely Pathogenic | -7.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.02 | Affected | 0.4850 | 0.2079 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.875C>A | A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -14.282 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.07 | Destabilizing | 1.2 | 3.82 | Destabilizing | 4.95 | Destabilizing | 1.54 | Destabilizing | 0.475 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 0.1444 | 0.2205 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.877C>G | R293G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. No tool suggests a benign effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | -15.861 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.70 | Destabilizing | 0.2 | 2.35 | Destabilizing | 3.03 | Destabilizing | 0.57 | Ambiguous | 0.604 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.45 | Pathogenic | 0.02 | Affected | 0.3235 | 0.3738 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.883A>C | T295P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -9.941 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 3.30 | Destabilizing | 1.78 | Ambiguous | 0.60 | Ambiguous | 0.531 | Likely Pathogenic | -4.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2442 | 0.5327 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.889A>G | K297E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as “Uncertain” and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, K297E is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -10.143 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 0.4 | 2.43 | Destabilizing | 2.21 | Destabilizing | 1.16 | Destabilizing | 0.507 | Likely Pathogenic | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | 0.4073 | 0.1547 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.895C>G | R299G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. With the majority of evidence pointing to a damaging effect, the variant is most likely pathogenic. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -8.354 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 3.58 | Destabilizing | 0.2 | 3.16 | Destabilizing | 3.37 | Destabilizing | 1.37 | Destabilizing | 0.248 | Likely Benign | -3.84 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.79 | Pathogenic | 0.02 | Affected | 0.3361 | 0.4150 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.896G>A | R299H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299H is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437801‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between pathogenic and uncertain calls. Overall, the majority of evidence points to a pathogenic 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. | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | Conflicting | 2 | 6-33437801-G-A | 10 | 6.20e-6 | -7.731 | In-Between | 0.388 | Ambiguous | Likely Benign | 3.97 | Destabilizing | 1.0 | 0.94 | Ambiguous | 2.46 | Destabilizing | 1.41 | Destabilizing | 0.238 | Likely Benign | -3.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 19 | 0.3293 | 0.2982 | 2 | 0 | 1.3 | -19.05 | 211.2 | 72.5 | -0.1 | 0.2 | -0.2 | 0.3 | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | ||||||||||||||
| c.896G>C | R299P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299P is not reported in ClinVar or gnomAD, indicating no publicly available frequency data. Prediction tools cluster into benign and pathogenic groups: benign predictions include REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b is uncertain. The SGM‑Consensus label is Likely Pathogenic. High‑accuracy tools give a clear signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta also predicts pathogenic. Overall, the predictions strongly favor a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.662 | In-Between | 0.722 | Likely Pathogenic | Likely Benign | 4.10 | Destabilizing | 0.2 | 3.01 | Destabilizing | 3.56 | Destabilizing | 1.19 | Destabilizing | 0.295 | Likely Benign | -4.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.68 | Pathogenic | 0.02 | Affected | 0.2072 | 0.5379 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.896G>T | R299L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of consensus predictions favor a pathogenic effect, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for R299L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -5.171 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 1.37 | Ambiguous | 0.6 | 0.77 | Ambiguous | 1.07 | Ambiguous | 0.59 | Ambiguous | 0.356 | Likely Benign | -4.03 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | 0.2027 | 0.5202 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.898T>C | S300P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300P is not 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 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The remaining tools—FoldX, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -7.379 | In-Between | 0.110 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 1.0 | 0.06 | Likely Benign | 0.65 | Ambiguous | 0.50 | Likely Benign | 0.086 | Likely Benign | -2.46 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.54 | Pathogenic | 0.02 | Affected | 0.2192 | 0.5585 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.905C>G | S302C 2D AIThe SynGAP1 missense variant S302C 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, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for S302C, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -7.290 | In-Between | 0.105 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.78 | Ambiguous | -0.04 | Likely Benign | 0.070 | Likely Benign | -0.83 | Neutral | 0.833 | Possibly Damaging | 0.455 | Possibly Damaging | 4.05 | Benign | 0.02 | Affected | 0.1221 | 0.6514 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.911A>C | D304A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304A variant has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify it as benign include premPS, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This prediction 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 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -6.258 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.77 | Ambiguous | 0.39 | Likely Benign | 0.523 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.80 | Pathogenic | 0.02 | Affected | 0.4457 | 0.6642 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.911A>G | D304G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304G 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, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta remaining uncertain. Overall, the majority of 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. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.713 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 1.02 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.99 | Ambiguous | 0.47 | Likely Benign | 0.380 | Likely Benign | -5.32 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.02 | Affected | 0.4590 | 0.6451 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.930G>C | E310D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E310D is reported in ClinVar (ID 975473.0) as Pathogenic and is not found in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, leaving no tool in the benign category. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports Pathogenic. The single uncertain result from FoldX is treated as unavailable. Overall, the variant is most likely pathogenic, and this assessment is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Likely Pathogenic | 1 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | 0.666 | Likely Pathogenic | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 0.1981 | 0.5222 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | ||||||||||||||||
| c.930G>T | E310D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL (Pathogenic), Rosetta (Pathogenic), Foldetta (Pathogenic), premPS (Pathogenic), PROVEAN (Pathogenic), polyPhen‑2 HumDiv (Pathogenic), polyPhen‑2 HumVar (Pathogenic), SIFT (Pathogenic), ESM1b (Pathogenic), FATHMM (Pathogenic), AlphaMissense‑Default (Pathogenic), and AlphaMissense‑Optimized (Pathogenic). No tool predicts a benign outcome; the only inconclusive result is FoldX (Uncertain). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for E310D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | 0.666 | Likely Pathogenic | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 0.1981 | 0.5222 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | ||||||||||||||||||
| c.931C>G | H311D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. The majority‑vote consensus (SGM‑Consensus) also reports it as likely pathogenic. Tools that evaluate structural stability give inconclusive results: FoldX, Rosetta, Foldetta, and premPS are listed as uncertain. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (derived from the same set of predictors) reports likely pathogenic, while Foldetta’s combined FoldX‑MD/Rosetta stability analysis remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, which is consistent with the absence of a benign ClinVar annotation and the lack of population frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -13.513 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.0 | 1.83 | Ambiguous | 1.55 | Ambiguous | 0.89 | Ambiguous | 0.633 | Likely Pathogenic | -6.94 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 0.2301 | 0.2008 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.931C>T | H311Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools with uncertain or inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Default—are treated as unavailable for pathogenicity assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the predictions are split, with five tools favoring benign, five favoring pathogenic, and three inconclusive. Based on the available evidence, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -4.513 | Likely Benign | 0.342 | Ambiguous | Likely Benign | -0.06 | Likely Benign | 0.2 | -1.58 | Ambiguous | -0.82 | Ambiguous | 0.18 | Likely Benign | 0.456 | Likely Benign | -3.80 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.86 | Pathogenic | 0.02 | Affected | 0.0965 | 0.4180 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.932A>T | H311L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311L 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 AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. Tools that predict a pathogenic outcome are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -10.119 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.53 | Ambiguous | 0.0 | -0.04 | Likely Benign | -0.29 | Likely Benign | 0.43 | Likely Benign | 0.663 | Likely Pathogenic | -7.99 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.87 | Pathogenic | 0.02 | Affected | 0.0961 | 0.5292 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.935T>A | F312Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a deleterious effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default, all of which classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide uncertain results. Overall, the majority of evidence points to a pathogenic 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 Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -7.571 | In-Between | 0.949 | Likely Pathogenic | Ambiguous | 1.04 | Ambiguous | 0.1 | 0.89 | Ambiguous | 0.97 | Ambiguous | 0.99 | Ambiguous | 0.744 | Likely Pathogenic | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 1.21 | Pathogenic | 0.02 | Affected | 0.1443 | 0.2728 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.937G>A | E313K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313K is listed in ClinVar as Benign (ClinVar ID 3695040.0) and is not reported in gnomAD. Prediction tools that report a benign effect are absent; all available predictors that provide a definitive call classify the variant as pathogenic. These include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Based on the overwhelming pathogenic predictions, the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | Likely Benign | 1 | -12.902 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.6 | 1.40 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | 0.575 | Likely Pathogenic | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2540 | 0.7708 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||
| c.938A>C | E313A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized, whereas the remaining pathogenic‑or‑likely‑pathogenic predictors are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -14.591 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 1.07 | Ambiguous | 0.3 | 0.97 | Ambiguous | 1.02 | Ambiguous | 0.62 | Ambiguous | 0.680 | Likely Pathogenic | -4.88 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.88 | Pathogenic | 0.02 | Affected | 0.3416 | 0.6743 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.941T>A | F314Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive—AlphaMissense‑Optimized, FoldX, and Foldetta—are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, while Foldetta’s combined stability analysis is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -13.297 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 1.33 | Ambiguous | 0.1 | 0.29 | Likely Benign | 0.81 | Ambiguous | 1.28 | Destabilizing | 0.374 | Likely Benign | -2.62 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 1.20 | Pathogenic | 0.02 | Affected | 0.1427 | 0.2173 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.946A>C | N316H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N316H is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts a benign effect; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (pathogenic), and PROVEAN (pathogenic), indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign impact. FoldX and premPS are inconclusive. Overall, the balance of evidence from the majority of prediction tools points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -8.141 | Likely Pathogenic | 0.440 | Ambiguous | Likely Benign | 0.72 | Ambiguous | 0.4 | 0.07 | Likely Benign | 0.40 | Likely Benign | 0.62 | Ambiguous | 0.306 | Likely Benign | -3.56 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.02 | Affected | 0.1555 | 0.7702 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.959T>G | V320G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two agreement groups: the single benign prediction comes from REVEL, while the pathogenic group includes FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Overall, the preponderance of evidence indicates that V320G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -9.043 | Likely Pathogenic | 0.816 | Likely Pathogenic | Ambiguous | 2.15 | Destabilizing | 1.1 | 1.87 | Ambiguous | 2.01 | Destabilizing | 1.48 | Destabilizing | 0.438 | Likely Benign | -5.74 | Deleterious | 0.958 | Probably Damaging | 0.999 | Probably Damaging | 1.89 | Pathogenic | 0.02 | Affected | 0.1688 | 0.1949 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.976C>T | H326Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for H326Y, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -10.896 | Likely Pathogenic | 0.855 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.4 | 0.25 | Likely Benign | 0.14 | Likely Benign | 0.07 | Likely Benign | 0.562 | Likely Pathogenic | -5.32 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.0796 | 0.4323 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.982T>C | Y328H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -10.885 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.0 | 2.43 | Destabilizing | 2.26 | Destabilizing | 1.35 | Destabilizing | 0.516 | Likely Pathogenic | -4.53 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.54 | Pathogenic | 0.02 | Affected | 0.2572 | 0.0703 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.988G>A | D330N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” while AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No folding‑stability methods (FoldX, Rosetta, premPS) provide decisive evidence. Overall, the preponderance of pathogenic predictions strongly suggests that D330N is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -12.993 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 1.61 | Ambiguous | 0.2 | 0.59 | Ambiguous | 1.10 | Ambiguous | 0.59 | Ambiguous | 0.350 | Likely Benign | -3.46 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 1.01 | Pathogenic | 0.02 | Affected | 0.1252 | 0.4263 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.995A>C | D332A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and Rosetta, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -12.290 | Likely Pathogenic | 0.876 | Likely Pathogenic | Ambiguous | 1.19 | Ambiguous | 0.2 | 0.32 | Likely Benign | 0.76 | Ambiguous | 0.54 | Ambiguous | 0.458 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.24 | Pathogenic | 0.02 | Affected | 0.2998 | 0.4176 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1000A>C | K334Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With seven tools favoring pathogenicity versus five favoring benign, the overall prediction leans toward pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -8.185 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.09 | Likely Benign | 0.46 | Likely Benign | 0.357 | Likely Benign | -3.67 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.74 | Pathogenic | 0.03 | Affected | 0.4519 | 0.1062 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1004G>A | R335H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335H is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33437909‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and Foldetta, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the preponderance of evidence points to a pathogenic impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | Uncertain | 1 | 6-33437909-G-A | 2 | 1.24e-6 | -12.521 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.58 | Ambiguous | 0.1 | 0.22 | Likely Benign | 0.40 | Likely Benign | 0.72 | Ambiguous | 0.132 | Likely Benign | -3.02 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.70 | Pathogenic | 0.03 | Affected | 3.38 | 22 | 0.2316 | 0.2330 | 2 | 0 | 1.3 | -19.05 | 242.4 | 82.1 | -2.4 | 0.6 | -0.1 | 0.1 | Uncertain | The guanidinium group of Arg335, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Ala322-Asp330, res. Gly341-Pro349), faces the post-synaptic inner membrane surface. In the WT simulations, the Arg335 side chain dynamically forms salt bridges with the carboxylate groups of Asp322, Asp338, and Asp616. In contrast, the imidazole ring of His335, which is not double protonated and thus not positively charged in the variant simulations, continues to move dynamically without forming any lasting or strong interactions. Importantly, the positively charged arginine residues of the C2 domain are ideal membrane anchors for ensuring SynGAP-membrane association. However, this phenomenon cannot be addressed using solvent-only simulations. | ||||||||||||||
| c.1015A>G | K339E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339E missense variant 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, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -14.284 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.05 | Likely Benign | 0.40 | Likely Benign | 0.482 | Likely Benign | -3.00 | Deleterious | 0.939 | Possibly Damaging | 0.670 | Possibly Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.3421 | 0.0882 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1024T>A | Y342N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342N has no ClinVar entry (ClinVar status: None) and is not reported in gnomAD (gnomAD ID: None). Prediction tools that assess the variant’s effect are overwhelmingly in agreement that it is deleterious: SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Taken together, 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 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | -9.685 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 1.76 | Ambiguous | 0.1 | 2.89 | Destabilizing | 2.33 | Destabilizing | 1.02 | Destabilizing | 0.554 | Likely Pathogenic | -6.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.71 | Pathogenic | 0.03 | Affected | 0.2189 | 0.0862 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1031G>T | G344V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -14.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 13.33 | Destabilizing | 1.5 | 14.51 | Destabilizing | 13.92 | Destabilizing | 0.53 | Ambiguous | 0.889 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.48 | Pathogenic | 0.03 | Affected | 0.1244 | 0.4744 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1034T>A | L345Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L345Q is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into benign (REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM). FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of predictions lean toward pathogenicity, while the single high‑accuracy tool that is definitive is benign. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -6.034 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.1 | 0.86 | Ambiguous | 1.09 | Ambiguous | 1.26 | Destabilizing | 0.218 | Likely Benign | -3.67 | Deleterious | 0.993 | Probably Damaging | 0.844 | Possibly Damaging | 1.82 | Pathogenic | 0.03 | Affected | 0.0937 | 0.0842 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
| c.1042G>A | V348M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V348M is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that report a clear outcome fall into two groups: benign calls come from REVEL, Foldetta, PROVEAN, and AlphaMissense‑Optimized; pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, ESM1b) give uncertain results, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority. High‑accuracy methods specifically show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus is not available. With four benign and four pathogenic predictions, the evidence is evenly split, providing no definitive direction. Therefore, the variant is not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | Uncertain | 1 | -7.076 | In-Between | 0.546 | Ambiguous | Likely Benign | -1.19 | Ambiguous | 0.1 | 0.72 | Ambiguous | -0.24 | Likely Benign | 0.76 | Ambiguous | 0.191 | Likely Benign | -1.62 | Neutral | 0.966 | Probably Damaging | 0.564 | Possibly Damaging | 1.58 | Pathogenic | 0.03 | Affected | 3.37 | 25 | 0.0903 | 0.4748 | 2 | 1 | -2.3 | 32.06 | 253.8 | -47.4 | -0.3 | 0.1 | 0.2 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val348, located in an anti-parallel β sheet strand (res. Gly341-Pro349), packs against multiple hydrophobic C2 domain residues (e.g., Leu353, Leu323, Leu402). In the variant simulations, the thioether side chain of Met348 can form similar interactions as valine due to its comparable hydrophobic profile. In fact, the thioether group of methionine can even stack favorably with the phenol ring of Tyr363 in the anti-parallel β sheet strand (res. Ala399-Ile411). Overall, the residue swap does not appear to cause negative effects on the protein structure based on the simulations. | |||||||||||||||||
| c.1051G>C | A351P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are Foldetta, PROVEAN, SIFT, FATHMM, and Rosetta. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar reporting; thus the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.559 | Likely Benign | 0.147 | Likely Benign | Likely Benign | -0.89 | Ambiguous | 0.2 | 6.19 | Destabilizing | 2.65 | Destabilizing | 0.62 | Ambiguous | 0.051 | Likely Benign | -3.08 | Deleterious | 0.016 | Benign | 0.007 | Benign | 1.67 | Pathogenic | 0.03 | Affected | 0.1862 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.1052C>T | A351V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351V is not reported in ClinVar and is absent from gnomAD. Computational predictions cluster into two groups: benign (REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar) and pathogenic (PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, FATHMM, SGM‑Consensus). High‑accuracy tools give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the balance of evidence leans toward a benign effect, but the presence of several pathogenic predictions introduces uncertainty. The variant is most likely benign based on the current computational data, 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 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -9.002 | Likely Pathogenic | 0.124 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.14 | Likely Benign | 0.29 | Likely Benign | 0.052 | Likely Benign | -2.84 | Deleterious | 0.915 | Possibly Damaging | 0.321 | Benign | 1.66 | Pathogenic | 0.03 | Affected | 0.1140 | 0.6565 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1057C>A | L353M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence 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 | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -6.943 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 1.28 | Ambiguous | 0.69 | Ambiguous | 0.60 | Ambiguous | 0.117 | Likely Benign | -0.47 | Neutral | 0.744 | Possibly Damaging | 0.289 | Benign | 1.33 | Pathogenic | 0.03 | Affected | 0.0847 | 0.4080 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1064G>C | G355A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G355A missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX and Foldetta are uncertain and therefore not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is uncertain. Consequently, the overall prediction leans toward a benign effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -5.431 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.88 | Ambiguous | 0.6 | 0.46 | Likely Benign | 0.67 | Ambiguous | 0.49 | Likely Benign | 0.286 | Likely Benign | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.03 | Affected | 0.4111 | 0.5045 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1078G>C | E360Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and premPS, while a majority of tools predict a pathogenic outcome: SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E360Q, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -11.012 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.1 | 1.38 | Ambiguous | 0.97 | Ambiguous | -0.02 | Likely Benign | 0.343 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 1.61 | Pathogenic | 0.03 | Affected | 0.1824 | 0.8282 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1115G>C | G372A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a benign impact for G372A, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -5.163 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 1.52 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.55 | Ambiguous | -0.12 | Likely Benign | 0.465 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.03 | Affected | 0.3956 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1127G>C | G376A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G376A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX and Rosetta give uncertain results and are not considered evidence for either side. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -6.016 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.3 | -0.84 | Ambiguous | 0.45 | Likely Benign | 0.00 | Likely Benign | 0.392 | Likely Benign | -0.44 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.33 | Pathogenic | 0.03 | Affected | 0.3868 | 0.4465 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1139G>A | G380E 2D AIThe SynGAP1 missense variant G380E has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized classifies the variant as benign, Foldetta predicts a pathogenic impact on protein stability, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools (7 benign vs. 6 pathogenic) lean toward a benign interpretation, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.334 | Likely Pathogenic | 0.617 | Likely Pathogenic | Likely Benign | 6.25 | Destabilizing | 5.1 | -0.28 | Likely Benign | 2.99 | Destabilizing | 0.24 | Likely Benign | 0.582 | Likely Pathogenic | -0.86 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.53 | Benign | 0.03 | Affected | 0.1585 | 0.3741 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1145G>A | G382E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438050‑G‑A). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact for G382E, 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 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | 6-33438050-G-A | -9.570 | Likely Pathogenic | 0.564 | Ambiguous | Likely Benign | 4.86 | Destabilizing | 1.7 | 6.64 | Destabilizing | 5.75 | Destabilizing | 0.48 | Likely Benign | 0.594 | Likely Pathogenic | -0.96 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 4.32 | 9 | 0.1775 | 0.3932 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||||
| c.1145G>T | G382V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G382V has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while premPS is uncertain. High‑accuracy assessments give a mixed signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, but Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy Foldetta result supports this. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -5.988 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 6.40 | Destabilizing | 1.6 | 9.28 | Destabilizing | 7.84 | Destabilizing | -0.53 | Ambiguous | 0.571 | Likely Pathogenic | -0.54 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 0.1631 | 0.3708 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1153T>A | S385T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumVar and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign effect. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | -5.904 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.35 | Likely Benign | -0.12 | Likely Benign | 0.214 | Likely Benign | -0.31 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.64 | Benign | 0.03 | Affected | 0.2266 | 0.6259 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1165T>A | S389T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389T is not reported in ClinVar and is present in gnomAD (variant ID 6‑33438070‑T‑A). Functional prediction tools that converge on a benign outcome include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 HumVar and SIFT predict a pathogenic effect. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign outcome. Taken together, the majority of evidence supports a benign classification for S389T, and this conclusion is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438070-T-A | -5.403 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.2 | 0.11 | Likely Benign | 0.24 | Likely Benign | -0.04 | Likely Benign | 0.242 | Likely Benign | -0.26 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 5.07 | Benign | 0.03 | Affected | 4.32 | 8 | 0.2317 | 0.6656 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.1171G>T | G391C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391C 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 AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and PROVEAN, whereas the remaining tools—REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—predict it to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a pathogenic effect. This prediction does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -8.596 | Likely Pathogenic | 0.123 | Likely Benign | Likely Benign | 2.65 | Destabilizing | 0.7 | 5.03 | Destabilizing | 3.84 | Destabilizing | 0.11 | Likely Benign | 0.640 | Likely Pathogenic | -1.29 | Neutral | 1.000 | Probably Damaging | 0.970 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 0.1483 | 0.4225 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1181A>G | K394R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K394R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only SIFT 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, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence supports a benign classification for K394R, and this conclusion does not contradict the absence of a ClinVar report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -4.902 | Likely Benign | 0.097 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.59 | Ambiguous | 0.42 | Likely Benign | 0.335 | Likely Benign | -1.97 | Neutral | 0.141 | Benign | 0.091 | Benign | 5.11 | Benign | 0.03 | Affected | 0.5488 | 0.2075 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||
| c.1184G>T | G395V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G395V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only FoldX and SIFT predict pathogenic. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is uncertain. Taken together, the preponderance of evidence points to a benign impact for G395V, 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 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -5.617 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 2.83 | Destabilizing | 0.7 | -0.37 | Likely Benign | 1.23 | Ambiguous | 0.08 | Likely Benign | 0.288 | Likely Benign | -1.49 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.21 | Benign | 0.03 | Affected | 0.1290 | 0.4183 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1192C>T | P398S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P398S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and SIFT. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of definitive predictions lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -6.757 | Likely Benign | 0.490 | Ambiguous | Likely Benign | 1.86 | Ambiguous | 0.3 | 1.78 | Ambiguous | 1.82 | Ambiguous | 0.85 | Ambiguous | 0.544 | Likely Pathogenic | -5.58 | Deleterious | 0.478 | Possibly Damaging | 0.130 | Benign | 5.68 | Benign | 0.03 | Affected | 0.3619 | 0.5737 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.1210G>C | A404P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A404P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, both polyPhen‑2 versions, and FATHMM, while pathogenic calls arise from FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -11.819 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 0.1 | 0.24 | Likely Benign | 1.64 | Ambiguous | 1.17 | Destabilizing | 0.227 | Likely Benign | -3.16 | Deleterious | 0.433 | Benign | 0.080 | Benign | 4.02 | Benign | 0.03 | Affected | 0.2271 | 0.6366 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1216T>C | Y406H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y406H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the preponderance of evidence indicates that Y406H is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.015 | Likely Pathogenic | 0.858 | Likely Pathogenic | Ambiguous | 2.13 | Destabilizing | 0.1 | 2.15 | Destabilizing | 2.14 | Destabilizing | 1.03 | Destabilizing | 0.239 | Likely Benign | -4.21 | Deleterious | 0.997 | Probably Damaging | 0.966 | Probably Damaging | 3.80 | Benign | 0.03 | Affected | 0.2666 | 0.0811 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1219C>G | Q407E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta 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 uncertain. Overall, the majority of tools and the SGM Consensus support a pathogenic classification, while a minority predict benign. No ClinVar entry exists to contradict these predictions. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -12.631 | Likely Pathogenic | 0.466 | Ambiguous | Likely Benign | 0.50 | Ambiguous | 0.1 | 1.68 | Ambiguous | 1.09 | Ambiguous | 1.30 | Destabilizing | 0.243 | Likely Benign | -2.66 | Deleterious | 0.989 | Probably Damaging | 0.930 | Probably Damaging | 3.96 | Benign | 0.03 | Affected | 0.1199 | 0.2000 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1241T>G | M414R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that M414R is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.404 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.1 | 2.58 | Destabilizing | 1.88 | Ambiguous | 1.45 | Destabilizing | 0.525 | Likely Pathogenic | -5.20 | Deleterious | 0.972 | Probably Damaging | 0.895 | Possibly Damaging | 3.38 | Benign | 0.03 | Affected | 0.1509 | 0.1037 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1243G>A | E415K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E415K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus shows AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall balance of predictions—particularly the two high‑accuracy pathogenic calls versus one benign—the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.433 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -0.07 | Likely Benign | 0.3 | -0.13 | Likely Benign | -0.10 | Likely Benign | 0.46 | Likely Benign | 0.326 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.22 | Benign | 0.03 | Affected | 0.2174 | 0.3860 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1244A>C | E415A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E415A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are given by FoldX and premPS. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy predictions support this view. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.743 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.33 | Likely Benign | 0.53 | Ambiguous | 0.435 | Likely Benign | -5.56 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.19 | Benign | 0.03 | Affected | 0.2909 | 0.3432 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1256A>C | E419A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -10.951 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.56 | Ambiguous | 0.1 | 0.94 | Ambiguous | 0.75 | Ambiguous | 0.28 | Likely Benign | 0.398 | Likely Benign | -5.60 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.4051 | 0.6705 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1259T>A | F420Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show mixed results. Benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are reported by premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments indicate that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.138 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.18 | Ambiguous | 0.1 | 0.96 | Ambiguous | 1.07 | Ambiguous | 1.31 | Destabilizing | 0.228 | Likely Benign | -2.80 | Deleterious | 0.306 | Benign | 0.100 | Benign | 3.09 | Benign | 0.03 | Affected | 0.1609 | 0.1498 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1264G>C | E422Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E422Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and FATHMM, while those that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. 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. | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -9.460 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.32 | Likely Benign | 0.0 | 0.21 | Likely Benign | 0.27 | Likely Benign | -0.15 | Likely Benign | 0.208 | Likely Benign | -2.26 | Neutral | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.38 | Benign | 0.03 | Affected | 0.1045 | 0.4913 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1268A>G | Y423C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -9.003 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 4.01 | Destabilizing | 0.1 | 4.49 | Destabilizing | 4.25 | Destabilizing | 1.84 | Destabilizing | 0.286 | Likely Benign | -7.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.03 | Affected | 0.2381 | 0.1096 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1273A>C | T425P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as deleterious, while only FATHMM predicts a benign outcome; premPS is uncertain. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Taken together, the overwhelming majority of evidence supports a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -12.318 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.3 | 6.49 | Destabilizing | 4.65 | Destabilizing | 0.77 | Ambiguous | 0.512 | Likely Pathogenic | -5.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.03 | Affected | 0.1815 | 0.3469 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1280A>G | H427R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427R is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438185‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT, while premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign stability change. No predictions or folding results are missing or inconclusive. Overall, the majority of evidence indicates the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | 6-33438185-A-G | -3.259 | Likely Benign | 0.439 | Ambiguous | Likely Benign | -0.04 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.22 | Likely Benign | 0.72 | Ambiguous | 0.168 | Likely Benign | -2.61 | Deleterious | 0.174 | Benign | 0.018 | Benign | 3.51 | Benign | 0.03 | Affected | 3.38 | 25 | 0.2108 | 0.2121 | 0 | 2 | -1.3 | 19.05 | |||||||||||||||||||||||||||
| c.1282T>A | Y428N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, which classifies the change as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -12.164 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 2.34 | Destabilizing | 0.0 | 3.81 | Destabilizing | 3.08 | Destabilizing | 1.85 | Destabilizing | 0.533 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.03 | Affected | 0.2607 | 0.0971 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1283A>C | Y428S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM. All other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -10.936 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 3.00 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.21 | Destabilizing | 2.00 | Destabilizing | 0.505 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.03 | Affected | 0.4623 | 0.2352 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1285C>T | R429W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438190‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward 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. | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | Conflicting | 5 | 6-33438190-C-T | 65 | 4.03e-5 | -10.666 | Likely Pathogenic | 0.500 | Ambiguous | Likely Benign | 0.31 | Likely Benign | 0.1 | -0.13 | Likely Benign | 0.09 | Likely Benign | 0.52 | Ambiguous | 0.282 | Likely Benign | -3.19 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 3.38 | 25 | 0.1232 | 0.3422 | 2 | -3 | 3.6 | 30.03 | 252.3 | 45.5 | 0.0 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg429, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or a H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, the indole ring of the Trp429 side chain cannot form ionic interactions with the acidic residues. Although it forms a H-bond with Ser471, the bonding is not as strong as that of arginine. The residue swap could affect the tertiary structure assembly during folding; however, no large-scale negative effects were seen during the simulations. | ||||||||||||||
| c.1294T>G | C432G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the absence 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 Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -10.247 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 1.37 | Ambiguous | 0.0 | 2.25 | Destabilizing | 1.81 | Ambiguous | 1.60 | Destabilizing | 0.631 | Likely Pathogenic | -11.46 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.03 | Affected | 0.2796 | 0.2130 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1307A>G | E436G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, premPS, and Foldetta are inconclusive. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta’s stability prediction is uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.355 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.02 | Destabilizing | 1.76 | Ambiguous | 0.58 | Ambiguous | 0.802 | Likely Pathogenic | -6.63 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 4.61 | Benign | 0.03 | Affected | 0.2910 | 0.4841 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1307A>T | E436V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436V variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -13.364 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.45 | Ambiguous | 0.0 | 1.62 | Ambiguous | 1.54 | Ambiguous | 0.30 | Likely Benign | 0.875 | Likely Pathogenic | -6.63 | Deleterious | 0.995 | Probably Damaging | 0.967 | Probably Damaging | 4.64 | Benign | 0.03 | Affected | 0.0727 | 0.5952 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1309C>G | P437A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, Rosetta, FATHMM, AlphaMissense‑Optimized, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Tools with uncertain or inconclusive results are AlphaMissense‑Default, FoldX, and Foldetta. High‑accuracy assessments give AlphaMissense‑Optimized a benign prediction. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic), yields a pathogenic consensus. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the balance of evidence leans toward a pathogenic effect for P437A, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -12.059 | Likely Pathogenic | 0.392 | Ambiguous | Likely Benign | 1.23 | Ambiguous | 0.0 | -3.14 | Stabilizing | -0.96 | Ambiguous | 0.50 | Likely Benign | 0.266 | Likely Benign | -6.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0.3489 | 0.4775 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.1310C>G | P437R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P437R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With the majority of tools indicating pathogenicity and the high‑accuracy consensus leaning toward pathogenic, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.094 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | -3.52 | Stabilizing | -1.59 | Ambiguous | 0.61 | Ambiguous | 0.461 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0.1448 | 0.2846 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1319A>T | N440I 2D AISynGAP1 missense variant N440I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, 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 | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.365 | Likely Pathogenic | 0.778 | Likely Pathogenic | Likely Benign | 0.97 | Ambiguous | 0.9 | 1.10 | Ambiguous | 1.04 | Ambiguous | 0.10 | Likely Benign | 0.100 | Likely Benign | -4.07 | Deleterious | 0.322 | Benign | 0.109 | Benign | 3.47 | Benign | 0.03 | Affected | 0.0554 | 0.3772 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1339G>T | V447F 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V447F 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, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect on protein folding. Overall, the majority of predictions lean toward pathogenicity, suggesting the variant is most likely pathogenic, a conclusion that does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -8.673 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 1.40 | Ambiguous | 0.3 | 0.61 | Ambiguous | 1.01 | Ambiguous | 0.20 | Likely Benign | 0.206 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.0551 | 0.3055 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||
| c.1381G>C | A461P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -13.869 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.1 | 5.09 | Destabilizing | 2.37 | Destabilizing | 0.84 | Ambiguous | 0.451 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.32 | Benign | 0.03 | Affected | 0.1748 | 0.3949 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1390T>A | F464I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -11.210 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.77 | Destabilizing | 0.2 | 4.35 | Destabilizing | 4.56 | Destabilizing | 1.23 | Destabilizing | 0.539 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1439 | 0.2002 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1397C>T | S466L 2D AIThe SynGAP1 missense variant S466L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, while the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Tools with uncertain or inconclusive results are AlphaMissense‑Optimized, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S466L. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -9.417 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | -0.36 | Likely Benign | 1.6 | -1.60 | Ambiguous | -0.98 | Ambiguous | -0.52 | Ambiguous | 0.768 | Likely Pathogenic | -3.05 | Deleterious | 0.995 | Probably Damaging | 0.991 | Probably Damaging | -1.56 | Pathogenic | 0.03 | Affected | 0.0666 | 0.4884 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.1400A>G | D467G 2D AISynGAP1 missense variant D467G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—including SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.973 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.8 | 2.55 | Destabilizing | 2.21 | Destabilizing | 0.23 | Likely Benign | 0.910 | Likely Pathogenic | -6.81 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0.3455 | 0.4908 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1412C>A | S471Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized scores the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, returns an uncertain stability change. No evidence from ClinVar contradicts these computational assessments. Overall, the preponderance of pathogenic predictions and the SGM Consensus suggest the variant is most likely pathogenic, consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -11.257 | Likely Pathogenic | 0.493 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | -1.31 | Ambiguous | -0.82 | Ambiguous | 0.19 | Likely Benign | 0.446 | Likely Benign | -4.79 | Deleterious | 0.980 | Probably Damaging | 0.584 | Possibly Damaging | -1.27 | Pathogenic | 0.03 | Affected | 0.0607 | 0.4417 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1414G>A | E472K 2D AIThe SynGAP1 missense variant E472K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.214 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.01 | Destabilizing | 1.2 | 3.23 | Destabilizing | 2.62 | Destabilizing | 0.78 | Ambiguous | 0.670 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 2.33 | Pathogenic | 0.03 | Affected | 0.3077 | 0.5651 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1439A>G | E480G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480G missense variant is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as pathogenic. Predictions that are uncertain—FoldX, premPS, and AlphaMissense‑Optimized—do not provide evidence for benignity. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic, and AlphaMissense‑Optimized remains uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -11.651 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 1.83 | Ambiguous | 0.1 | 2.34 | Destabilizing | 2.09 | Destabilizing | 0.65 | Ambiguous | 0.778 | Likely Pathogenic | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0.2806 | 0.6172 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1447A>G | I483V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions marked as uncertain include FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, whereas Foldetta remains uncertain. Overall, the balance of evidence from both general and high‑accuracy tools leans toward a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | Conflicting | 2 | -10.121 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 1.00 | Ambiguous | 0.0 | 0.27 | Likely Benign | 0.64 | Ambiguous | 1.02 | Destabilizing | 0.228 | Likely Benign | -0.86 | Neutral | 0.914 | Possibly Damaging | 0.921 | Probably Damaging | 3.23 | Benign | 0.03 | Affected | 3.37 | 32 | 0.0876 | 0.2691 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||
| c.1468G>A | A490T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490T is listed in gnomAD (variant ID 6‑33438500‑G‑A) but has no ClinVar entry. Prediction tools that agree on a pathogenic effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta is also uncertain. Based on the preponderance of pathogenic predictions and the lack of any benign calls, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | 6-33438500-G-A | 1 | 6.20e-7 | -10.266 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 1.70 | Ambiguous | 1.25 | Ambiguous | 1.00 | Destabilizing | 0.821 | Likely Pathogenic | -3.87 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.34 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.1065 | 0.4495 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.1490A>C | Y497S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497S is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized) classifies the change as pathogenic, leaving no benign predictions. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -13.171 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.1 | 4.68 | Destabilizing | 4.17 | Destabilizing | 2.22 | Destabilizing | 0.814 | Likely Pathogenic | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.64 | Pathogenic | 0.03 | Affected | 0.3770 | 0.1419 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1490A>G | Y497C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic. No tool reports a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as “Pathogenic.” Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | 0.806 | Likely Pathogenic | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.2905 | 0.1488 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | |||||||||||||||
| c.1499T>G | L500R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as pathogenic include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a benign effect; the benign group is empty. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overwhelming agreement among pathogenic predictors and the lack of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -15.576 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 2.23 | Destabilizing | 0.1 | 1.04 | Ambiguous | 1.64 | Ambiguous | 1.11 | Destabilizing | 0.794 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.02 | Pathogenic | 0.03 | Affected | 0.1204 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1501A>T | I501F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I501F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain (a stability method that integrates FoldX‑MD and Rosetta outputs). No predictions are missing or inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -12.113 | Likely Pathogenic | 0.664 | Likely Pathogenic | Likely Benign | 3.06 | Destabilizing | 0.1 | 0.26 | Likely Benign | 1.66 | Ambiguous | 0.71 | Ambiguous | 0.385 | Likely Benign | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.0574 | 0.1594 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1508A>C | Q503P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; the remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Because the majority of evidence points to a deleterious effect, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -10.915 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 1.06 | Ambiguous | 0.7 | 5.94 | Destabilizing | 3.50 | Destabilizing | 0.75 | Ambiguous | 0.860 | Likely Pathogenic | -5.20 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | -1.53 | Pathogenic | 0.03 | Affected | 0.2076 | 0.3610 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1520A>T | K507M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507M 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 FoldX, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, more tools (8) predict pathogenicity than benign (5), and the high‑accuracy consensus leans toward pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -9.548 | Likely Pathogenic | 0.576 | Likely Pathogenic | Likely Benign | 0.12 | Likely Benign | 0.1 | -0.74 | Ambiguous | -0.31 | Likely Benign | -0.22 | Likely Benign | 0.850 | Likely Pathogenic | -2.39 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.63 | Pathogenic | 0.03 | Affected | 0.0783 | 0.2251 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1538T>G | F513C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -11.389 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.3 | 4.20 | Destabilizing | 4.06 | Destabilizing | 1.64 | Destabilizing | 0.919 | Likely Pathogenic | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0.2384 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1544G>C | R515P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515P has no ClinVar entry and is absent from gnomAD. In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not reported, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -14.291 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.1 | 8.87 | Destabilizing | 6.28 | Destabilizing | 1.02 | Destabilizing | 0.823 | Likely Pathogenic | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0.2223 | 0.2725 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1552T>G | Y518D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.247 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.9 | 2.68 | Destabilizing | 3.30 | Destabilizing | 1.36 | Destabilizing | 0.619 | Likely Pathogenic | -9.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.3682 | 0.0212 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1555G>A | E519K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519K missense variant is listed in gnomAD (ID 6‑33438798‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E519K, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | 6-33438798-G-A | 1 | 6.20e-7 | -13.532 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | -0.55 | Ambiguous | 0.0 | -0.60 | Ambiguous | -0.58 | Ambiguous | 0.06 | Likely Benign | 0.328 | Likely Benign | -3.48 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 3.28 | Benign | 0.03 | Affected | 3.37 | 35 | 0.2545 | 0.3379 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1559C>G | S520C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520C is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default; Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -6.947 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.2 | 0.76 | Ambiguous | 0.41 | Likely Benign | 0.53 | Ambiguous | 0.720 | Likely Pathogenic | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0.1029 | 0.4948 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1595C>T | T532I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) reports a benign effect. Overall, the balance of evidence leans toward pathogenicity, 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 | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -9.031 | Likely Pathogenic | 0.591 | Likely Pathogenic | Likely Benign | -0.11 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.38 | Likely Benign | 0.22 | Likely Benign | 0.428 | Likely Benign | -3.31 | Deleterious | 0.633 | Possibly Damaging | 0.202 | Benign | -1.31 | Pathogenic | 0.03 | Affected | 0.0713 | 0.4983 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1613A>G | E538G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E538G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability result is definitive. Overall, the balance of evidence, including the majority‑vote SGM Consensus and the higher number of pathogenic predictions, points to a pathogenic effect for E538G. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.033501 | Uncertain | 0.938 | 0.359 | 0.000 | -9.258 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.91 | Ambiguous | 0.0 | 1.07 | Ambiguous | 0.99 | Ambiguous | 0.31 | Likely Benign | 0.285 | Likely Benign | -5.10 | Deleterious | 0.993 | Probably Damaging | 0.700 | Possibly Damaging | 3.33 | Benign | 0.03 | Affected | 0.3173 | 0.3713 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1620G>C | Q540H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool predicts a benign effect. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the evidence strongly favors a pathogenic impact for Q540H, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -12.730 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 1.79 | Ambiguous | 0.6 | 1.46 | Ambiguous | 1.63 | Ambiguous | 0.72 | Ambiguous | 0.832 | Likely Pathogenic | -4.97 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.03 | Affected | 0.1179 | 0.2072 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1620G>T | Q540H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q540H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool predicts a benign effect. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the evidence strongly favors a pathogenic impact for Q540H, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -12.730 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 1.79 | Ambiguous | 0.6 | 1.46 | Ambiguous | 1.63 | Ambiguous | 0.72 | Ambiguous | 0.832 | Likely Pathogenic | -4.97 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.03 | Affected | 0.1179 | 0.2072 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1677C>G | C559W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C559W is not listed in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM Consensus is Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Benign. Overall, seven of the twelve evaluated tools predict pathogenicity versus six benign, giving a slight majority toward a deleterious effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -12.765 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.19 | Likely Benign | 0.0 | 0.01 | Likely Benign | -0.09 | Likely Benign | 0.44 | Likely Benign | 0.274 | Likely Benign | -8.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.42 | Benign | 0.03 | Affected | 0.2492 | 0.2135 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1693C>G | L565V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L565V has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Two tools (AlphaMissense‑Optimized and Rosetta) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic impact on protein stability. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.045819 | Uncertain | 0.922 | 0.205 | 0.000 | -11.118 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 2.69 | Destabilizing | 0.0 | 1.37 | Ambiguous | 2.03 | Destabilizing | 1.40 | Destabilizing | 0.303 | Likely Benign | -2.99 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.87 | Benign | 0.03 | Affected | 0.1558 | 0.2488 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1698G>C | K566N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K566N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while Rosetta is uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Consequently, the variant is most likely pathogenic based on the available 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 Pathogenic | GAP | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | -11.255 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.83 | Destabilizing | 0.3 | 1.33 | Ambiguous | 2.08 | Destabilizing | 1.32 | Destabilizing | 0.683 | Likely Pathogenic | -4.04 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.3042 | 0.1567 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.1698G>T | K566N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K566N is listed in gnomAD (variant ID 6‑33440750‑G‑T) but has no ClinVar entry. All available in‑silico predictors that provide a definitive call classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tool with an inconclusive result is Rosetta (Uncertain), which is treated as unavailable evidence. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on current predictions, and this conclusion does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | 6-33440750-G-T | -11.255 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.83 | Destabilizing | 0.3 | 1.33 | Ambiguous | 2.08 | Destabilizing | 1.32 | Destabilizing | 0.683 | Likely Pathogenic | -4.04 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0.3042 | 0.1567 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||||
| c.1709C>A | A570D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A570D is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -14.117 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.47 | Destabilizing | 1.2 | 2.33 | Destabilizing | 2.40 | Destabilizing | 1.36 | Destabilizing | 0.805 | Likely Pathogenic | -5.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.28 | Pathogenic | 0.03 | Affected | 0.2006 | 0.2206 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1738G>C | G580R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a pathogenic outcome. No tool predicts a benign effect. Several methods return uncertain results—Rosetta, Foldetta (combining FoldX‑MD and Rosetta outputs), and premPS—so these do not influence the overall assessment. High‑accuracy evaluations reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -11.459 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 2.20 | Destabilizing | 0.1 | 1.26 | Ambiguous | 1.73 | Ambiguous | 0.81 | Ambiguous | 0.623 | Likely Pathogenic | -7.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.03 | Affected | 0.1009 | 0.3197 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1747G>C | D583H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D583H is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. FoldX and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -9.191 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | -0.07 | Likely Benign | 0.58 | Ambiguous | -0.22 | Likely Benign | 0.713 | Likely Pathogenic | -6.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 0.1217 | 0.4182 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1748A>G | D583G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583G missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and ESM1b, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—classify it as pathogenic. Uncertain results come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessment shows the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and AlphaMissense‑Optimized remains inconclusive; Foldetta also reports no definitive stability change. Overall, the preponderance of evidence points to a pathogenic effect for D583G, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -6.765 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 1.10 | Ambiguous | 0.2 | 0.56 | Ambiguous | 0.83 | Ambiguous | 0.10 | Likely Benign | 0.850 | Likely Pathogenic | -6.77 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.43 | Pathogenic | 0.03 | Affected | 0.3072 | 0.4284 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1751T>G | I584S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I584S missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. No contradictory evidence is present. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | -13.379 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 3.15 | Destabilizing | 0.1 | 2.53 | Destabilizing | 2.84 | Destabilizing | 1.70 | Destabilizing | 0.710 | Likely Pathogenic | -5.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.18 | Pathogenic | 0.03 | Affected | 0.2391 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1780T>C | F594L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. In the high‑accuracy subset, AlphaMissense‑Optimized remains pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is uncertain. No tools predict a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -11.270 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.41 | Destabilizing | 1.96 | Ambiguous | 1.56 | Destabilizing | 0.940 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.98 | Pathogenic | 0.03 | Affected | 0.1790 | 0.2439 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1781T>G | F594C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. All available evidence points to a damaging effect. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -14.591 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.0 | 4.35 | Destabilizing | 4.16 | Destabilizing | 1.36 | Destabilizing | 0.943 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.05 | Pathogenic | 0.03 | Affected | 0.2595 | 0.0615 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1782C>A | F594L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. In the high‑accuracy subset, AlphaMissense‑Optimized remains pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is uncertain. No tools predict a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -11.270 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.41 | Destabilizing | 1.96 | Ambiguous | 1.56 | Destabilizing | 0.893 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.98 | Pathogenic | 0.03 | Affected | 0.1790 | 0.2439 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1782C>G | F594L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity; SGM‑Consensus also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. Stability‑focused methods give mixed results: FoldX is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, so these do not provide decisive evidence. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Overall, the consensus of available predictions strongly suggests that F594L is most likely pathogenic, 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 Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -11.270 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.50 | Ambiguous | 0.1 | 2.41 | Destabilizing | 1.96 | Ambiguous | 1.56 | Destabilizing | 0.893 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.98 | Pathogenic | 0.03 | Affected | 0.1790 | 0.2439 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1795T>G | C599G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the evidence strongly favors a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.342 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 1.40 | Ambiguous | 0.0 | 0.90 | Ambiguous | 1.15 | Ambiguous | 1.43 | Destabilizing | 0.923 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.03 | Affected | 0.2444 | 0.2130 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1798C>G | P600A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from Rosetta and premPS, while the remaining 11 tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain result. Taken together, the overwhelming majority of evidence indicates that P600A is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -11.385 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.0 | -3.30 | Stabilizing | -0.57 | Ambiguous | 0.39 | Likely Benign | 0.581 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.38 | Pathogenic | 0.03 | Affected | 0.3692 | 0.4132 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1802C>T | A601V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601V is listed in ClinVar (ID 968190.0) with an uncertain clinical significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Uncertain | 1 | -10.447 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 1.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 1.00 | Ambiguous | 0.81 | Ambiguous | 0.535 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.74 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1338 | 0.5263 | 0 | 0 | 2.4 | 28.05 | 228.5 | -45.5 | 0.0 | 0.0 | 0.4 | 0.5 | X | Potentially Benign | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, 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.1804A>G | I602V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, SIFT, and FATHMM. Uncertain or inconclusive results come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis remains 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. | Likely Benign | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -6.317 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 0.0 | 0.78 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | 0.309 | Likely Benign | -0.84 | Neutral | 0.528 | Possibly Damaging | 0.179 | Benign | -1.89 | Pathogenic | 0.03 | Affected | 0.1173 | 0.3326 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1809G>A | M603I 2D AIThe SynGAP1 missense variant M603I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence points to a pathogenic effect for M603I, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.086 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.6 | 0.07 | Likely Benign | 0.44 | Likely Benign | -0.07 | Likely Benign | 0.699 | Likely Pathogenic | -3.32 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.21 | Pathogenic | 0.03 | Affected | 0.1208 | 0.2350 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1809G>C | M603I 2D AIThe SynGAP1 missense variant M603I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for M603I. 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.086 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.6 | 0.07 | Likely Benign | 0.44 | Likely Benign | -0.07 | Likely Benign | 0.699 | Likely Pathogenic | -3.32 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.21 | Pathogenic | 0.03 | Affected | 0.1208 | 0.2350 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1809G>T | M603I 2D AIThe SynGAP1 missense variant M603I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for M603I. 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.086 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.6 | 0.07 | Likely Benign | 0.44 | Likely Benign | -0.07 | Likely Benign | 0.698 | Likely Pathogenic | -3.32 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.21 | Pathogenic | 0.03 | Affected | 0.1208 | 0.2350 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1817G>C | S606T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools predict pathogenicity, and the SGM Consensus supports this view, while the high‑accuracy methods give mixed results. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.052 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.06 | Likely Benign | 0.1 | -0.91 | Ambiguous | -0.43 | Likely Benign | 0.57 | Ambiguous | 0.203 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.933 | Probably Damaging | 3.34 | Benign | 0.03 | Affected | 0.1260 | 0.4513 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1832T>A | M611K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M611K variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. The majority of other in silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic effect; FoldX is uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -13.021 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 1.86 | Ambiguous | 0.6 | 2.65 | Destabilizing | 2.26 | Destabilizing | 1.65 | Destabilizing | 0.665 | Likely Pathogenic | -4.10 | Deleterious | 0.250 | Benign | 0.120 | Benign | -1.26 | Pathogenic | 0.03 | Affected | 0.1193 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1838A>T | E613V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E613V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are Foldetta and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. FoldX and Rosetta give uncertain results and are not included in the agreement groups. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Because the majority of evidence points to a deleterious effect, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -12.799 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.5 | -0.76 | Ambiguous | -0.02 | Likely Benign | 0.31 | Likely Benign | 0.767 | Likely Pathogenic | -6.57 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | -1.25 | Pathogenic | 0.03 | Affected | 0.0935 | 0.6565 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1846G>C | D616H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616H missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that agree on a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results—Rosetta and AlphaMissense‑Optimized—so their outputs are treated as unavailable for inference. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is Pathogenic. Overall, the majority of evidence points to a pathogenic effect. The variant’s predicted pathogenicity does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -9.815 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 2.13 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.01 | Destabilizing | 0.45 | Likely Benign | 0.316 | Likely Benign | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.952 | Probably Damaging | 3.30 | Benign | 0.03 | Affected | 0.1330 | 0.4273 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1848T>A | D616E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D616E missense variant is catalogued in gnomAD (ID 6‑33440900‑T‑A) but has no ClinVar submission. Functional prediction tools show a split assessment: benign calls come from REVEL, both polyPhen‑2 HumDiv and HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, SIFT, and AlphaMissense‑Default. The remaining predictors (FoldX, Rosetta, Foldetta, premPS, ESM1b) are inconclusive. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, and Foldetta, which evaluates protein‑folding stability, is uncertain. Overall, the majority of evidence leans toward pathogenicity, and this conclusion does not conflict with ClinVar because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | 6-33440900-T-A | 1 | 6.20e-7 | -7.250 | In-Between | 0.695 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.24 | Ambiguous | 0.58 | Ambiguous | 0.092 | Likely Benign | -2.85 | Deleterious | 0.421 | Benign | 0.232 | Benign | 3.32 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1225 | 0.4128 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1848T>G | D616E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D616E is not reported in ClinVar but is present in gnomAD (ID 6‑33440900‑T‑G). Functional prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, SIFT, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of conventional predictors lean toward a benign effect, but the high‑accuracy consensus is split, leaving the variant’s clinical significance unresolved. Thus, the variant is most likely benign based on the bulk of predictions, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | 6-33440900-T-G | 3 | 1.86e-6 | -7.250 | In-Between | 0.695 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.24 | Ambiguous | 0.58 | Ambiguous | 0.092 | Likely Benign | -2.85 | Deleterious | 0.421 | Benign | 0.232 | Benign | 3.32 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1225 | 0.4128 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1856C>T | T619I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Based on the consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -11.760 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | -1.06 | Ambiguous | 0.1 | -1.35 | Ambiguous | -1.21 | Ambiguous | 0.58 | Ambiguous | 0.735 | Likely Pathogenic | -5.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0.0869 | 0.4377 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1870A>G | T624A 2D AIThe SynGAP1 T624A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FoldX and Foldetta, while the majority of tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic outcome. Uncertain predictions come from AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect for T624A, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -12.967 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | -0.38 | Likely Benign | 0.4 | 0.51 | Ambiguous | 0.07 | Likely Benign | 0.80 | Ambiguous | 0.895 | Likely Pathogenic | -4.94 | Deleterious | 0.962 | Probably Damaging | 0.694 | Possibly Damaging | -1.45 | Pathogenic | 0.03 | Affected | 0.2903 | 0.2872 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1897C>G | L633V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633V is not reported in ClinVar and is present in the gnomAD database (ID 6‑33440949‑C‑G). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus, and Foldetta; the Rosetta score is uncertain and therefore not considered. High‑accuracy methods give a pathogenic consensus: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic impact for L633V, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | 6-33440949-C-G | 1 | 6.20e-7 | -9.992 | Likely Pathogenic | 0.760 | Likely Pathogenic | Likely Benign | 2.32 | Destabilizing | 0.2 | 1.71 | Ambiguous | 2.02 | Destabilizing | 1.32 | Destabilizing | 0.327 | Likely Benign | -2.99 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.86 | Benign | 0.03 | Affected | 3.37 | 34 | 0.1517 | 0.2766 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1906T>A | F636I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.031 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.96 | Destabilizing | 0.2 | 4.57 | Destabilizing | 3.77 | Destabilizing | 1.10 | Destabilizing | 0.501 | Likely Pathogenic | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.977 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1660 | 0.2153 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1907T>C | F636S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all predict a pathogenic impact. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.290 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.08 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.37 | Destabilizing | 1.51 | Destabilizing | 0.559 | Likely Pathogenic | -7.50 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.3877 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1909T>C | S637P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments give a pathogenic signal: the SGM Consensus predicts likely pathogenic, Foldetta predicts destabilizing pathogenic effects, whereas AlphaMissense‑Optimized remains uncertain. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -11.455 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 6.73 | Destabilizing | 0.1 | 6.36 | Destabilizing | 6.55 | Destabilizing | 0.44 | Likely Benign | 0.192 | Likely Benign | -3.12 | Deleterious | 0.946 | Possibly Damaging | 0.360 | Benign | 3.36 | Benign | 0.03 | Affected | 0.2374 | 0.4094 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1913A>C | K638T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638T is not reported in ClinVar and is absent from gnomAD. Consensus from standard in silico predictors shows a split: benign calls come from REVEL, Rosetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; FoldX and Foldetta are inconclusive. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic effect for K638T. This prediction is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -8.856 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.55 | Ambiguous | 0.07 | Likely Benign | 0.404 | Likely Benign | -5.39 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.52 | Benign | 0.03 | Affected | 0.1632 | 0.2619 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1915T>C | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen2_HumVar, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Based on the majority of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.499 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1916T>A | F639Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed signal: AlphaMissense‑Optimized classifies the change as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.762 | Likely Pathogenic | 0.670 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.1 | 0.99 | Ambiguous | 1.46 | Ambiguous | 1.20 | Destabilizing | 0.330 | Likely Benign | -2.99 | Deleterious | 0.930 | Possibly Damaging | 0.263 | Benign | 3.06 | Benign | 0.03 | Affected | 0.1530 | 0.1635 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1917T>A | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen2_HumVar, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Based on the majority of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.336 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1917T>G | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas a majority of tools predict pathogenicity: SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta and Foldetta. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the balance of evidence points to a pathogenic effect for F639L, and this assessment does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.336 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1924A>G | K642E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K642E is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No prediction is inconclusive. Overall, the majority of tools lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.287 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.1 | -0.13 | Likely Benign | 0.07 | Likely Benign | 0.40 | Likely Benign | 0.404 | Likely Benign | -3.92 | Deleterious | 0.116 | Benign | 0.011 | Benign | 2.96 | Benign | 0.03 | Affected | 0.3865 | 0.1013 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1933T>C | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this view. Overall, the majority of computational evidence points to a pathogenic impact for F645L, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.264 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1934T>C | F645S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F645S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while both the SGM Consensus and Foldetta predict pathogenicity. No evidence from ClinVar contradicts these findings. Overall, the preponderance of predictions supports a pathogenic classification for F645S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -9.748 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 2.49 | Destabilizing | 0.2 | 2.30 | Destabilizing | 2.40 | Destabilizing | 1.57 | Destabilizing | 0.326 | Likely Benign | -5.34 | Deleterious | 0.755 | Possibly Damaging | 0.112 | Benign | 3.37 | Benign | 0.03 | Affected | 0.3899 | 0.0547 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1935T>A | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this view. Overall, the majority of computational evidence points to a pathogenic impact for F645L, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.159 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1935T>G | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact fall into two groups: benign predictions are made by REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM; pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. No evidence from FoldX‑MD, Rosetta, or premPS is available to alter this conclusion. Overall, the majority of computational evidence points to a pathogenic impact for F645L, and this assessment is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.159 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1936C>G | L646V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM, whereas pathogenic predictions arise from FoldX, Rosetta, premPS, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs 1 pathogenic votes). High‑accuracy assessments further indicate AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -8.995 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 3.82 | Destabilizing | 0.2 | 2.01 | Destabilizing | 2.92 | Destabilizing | 1.41 | Destabilizing | 0.125 | Likely Benign | -1.40 | Neutral | 0.040 | Benign | 0.021 | Benign | 3.21 | Benign | 0.03 | Affected | 0.2200 | 0.3767 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1937T>G | L646R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the preponderance of evidence points to a pathogenic effect for L646R, 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 | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.393 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 4.44 | Destabilizing | 0.2 | 3.94 | Destabilizing | 4.19 | Destabilizing | 2.75 | Destabilizing | 0.455 | Likely Benign | -3.56 | Deleterious | 0.014 | Benign | 0.002 | Benign | 3.17 | Benign | 0.03 | Affected | 0.2304 | 0.1405 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1943T>G | F648C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F648C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM predict pathogenicity, while FATHMM alone predicts benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. In summary, the overwhelming consensus from both general and high‑accuracy predictors is that F648C is pathogenic. This conclusion is consistent with the absence of any ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -10.547 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.28 | Destabilizing | 0.1 | 3.35 | Destabilizing | 3.32 | Destabilizing | 1.22 | Destabilizing | 0.621 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 0.2283 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1948A>G | N650D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. The variant is most likely pathogenic based on the consensus of predictive tools, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -14.267 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.14 | Ambiguous | 0.3 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.389 | Likely Benign | -4.98 | Deleterious | 0.591 | Possibly Damaging | 0.185 | Benign | 2.99 | Benign | 0.03 | Affected | 0.2320 | 0.2973 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1948A>T | N650Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -16.923 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.44 | Ambiguous | 0.16 | Likely Benign | 0.587 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 3.03 | Benign | 0.03 | Affected | 0.0852 | 0.3865 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1950T>A | N650K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.1950T>G | N650K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650K is not reported in ClinVar and is present in gnomAD (ID 6‑33441209‑T‑G). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and Foldetta, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and Rosetta) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, indicating the variant is most likely pathogenic, and this is consistent with the lack of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | 6-33441209-T-G | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1966G>A | E656K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656K has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -13.833 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -1.06 | Ambiguous | 0.0 | 0.02 | Likely Benign | -0.52 | Ambiguous | 0.16 | Likely Benign | 0.502 | Likely Pathogenic | -3.49 | Deleterious | 0.985 | Probably Damaging | 0.553 | Possibly Damaging | 3.44 | Benign | 0.03 | Affected | 0.3001 | 0.6406 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1967A>C | E656A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further reveal that AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing or inconclusive. Based on the overall evidence, the variant is most likely pathogenic; this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -14.373 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.12 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.11 | Likely Benign | -0.13 | Likely Benign | 0.499 | Likely Benign | -5.38 | Deleterious | 0.985 | Probably Damaging | 0.755 | Possibly Damaging | 3.46 | Benign | 0.03 | Affected | 0.4244 | 0.6271 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1971G>C | W657C 2D AISynGAP1 missense variant W657C 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 and FATHMM. Those that predict a deleterious effect are FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta reports an uncertain outcome. High‑accuracy assessments further support a damaging interpretation: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that W657C is most likely pathogenic, which 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 Pathogenic | GAP | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | Uncertain | 1 | -12.035 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.74 | Destabilizing | 0.3 | 1.69 | Ambiguous | 2.22 | Destabilizing | 1.30 | Destabilizing | 0.463 | Likely Benign | -11.06 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 3.43 | Benign | 0.03 | Affected | 0.3834 | 0.0766 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||
| c.1971G>T | W657C 2D AIThe SynGAP1 W657C missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Foldetta also supports pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments further reinforce a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the preponderance of evidence points to the variant being most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -12.035 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.74 | Destabilizing | 0.3 | 1.69 | Ambiguous | 2.22 | Destabilizing | 1.30 | Destabilizing | 0.463 | Likely Benign | -11.06 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 3.43 | Benign | 0.03 | Affected | 0.3834 | 0.0766 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.1978A>C | M660L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M660L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions are missing or inconclusive. Overall, the balance of evidence leans toward a benign classification, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -12.576 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | 0.16 | Likely Benign | 0.0 | -0.10 | Likely Benign | 0.03 | Likely Benign | 0.97 | Ambiguous | 0.330 | Likely Benign | -2.99 | Deleterious | 0.596 | Possibly Damaging | 0.101 | Benign | 3.56 | Benign | 0.03 | Affected | 0.1337 | 0.3891 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1978A>T | M660L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M660L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions are missing or inconclusive. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -12.576 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | 0.16 | Likely Benign | 0.0 | -0.10 | Likely Benign | 0.03 | Likely Benign | 0.97 | Ambiguous | 0.330 | Likely Benign | -2.99 | Deleterious | 0.596 | Possibly Damaging | 0.101 | Benign | 3.56 | Benign | 0.03 | Affected | 0.1337 | 0.3891 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1981C>G | Q661E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661E is not 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, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of available predictions lean toward a benign impact. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -12.121 | Likely Pathogenic | 0.370 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 0.50 | Ambiguous | 0.61 | Ambiguous | 0.141 | Likely Benign | -2.15 | Neutral | 0.988 | Probably Damaging | 0.619 | Possibly Damaging | 3.42 | Benign | 0.03 | Affected | 0.1199 | 0.2439 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1992G>C | L664F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664F resides in the GAP domain. ClinVar lists no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -12.834 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.98 | Ambiguous | 0.3 | 1.03 | Ambiguous | 1.51 | Ambiguous | 0.55 | Ambiguous | 0.355 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.05 | Benign | 0.03 | Affected | 0.0537 | 0.2311 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1992G>T | L664F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664F resides in the GAP domain. ClinVar lists no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -12.834 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.98 | Ambiguous | 0.3 | 1.03 | Ambiguous | 1.51 | Ambiguous | 0.55 | Ambiguous | 0.355 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.05 | Benign | 0.03 | Affected | 0.0537 | 0.2311 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1997A>T | E666V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools show mixed results: benign calls come from REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. FoldX alone is uncertain. Overall, the majority of tools and the high‑accuracy consensus favor a pathogenic interpretation, with no conflict from ClinVar status because no classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -10.870 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.35 | Likely Benign | 0.31 | Likely Benign | 0.476 | Likely Benign | -5.95 | Deleterious | 0.575 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.03 | Affected | 0.0818 | 0.5613 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2007T>A | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2007T>G | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus concurs, and the Foldetta stability analysis is inconclusive and therefore not used as evidence. No other tools provide definitive support for benignity. Consequently, the preponderance of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2012A>C | D671A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671A missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with seven tools supporting pathogenicity versus four supporting benignity. This conclusion does not conflict with ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.709 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.1 | 0.79 | Ambiguous | 0.52 | Ambiguous | 0.10 | Likely Benign | 0.245 | Likely Benign | -5.08 | Deleterious | 0.980 | Probably Damaging | 0.804 | Possibly Damaging | 3.34 | Benign | 0.03 | Affected | 0.4056 | 0.5895 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.2018T>A | L673Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX and Foldetta, as well as AlphaMissense‑Default, are inconclusive and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.104692 | Uncertain | 0.545 | 0.369 | 0.000 | -11.963 | Likely Pathogenic | 0.445 | Ambiguous | Likely Benign | 1.56 | Ambiguous | 0.2 | 2.32 | Destabilizing | 1.94 | Ambiguous | 1.02 | Destabilizing | 0.190 | Likely Benign | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.1045 | 0.1172 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
| c.2018T>G | L673R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L673R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). FoldX and Foldetta are inconclusive. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus, and an uncertain outcome from Foldetta. Overall, the majority of evidence points toward pathogenicity, and this conclusion does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.104692 | Uncertain | 0.545 | 0.369 | 0.000 | -14.474 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 1.10 | Ambiguous | 0.2 | 2.04 | Destabilizing | 1.57 | Ambiguous | 1.23 | Destabilizing | 0.178 | Likely Benign | -3.81 | Deleterious | 0.991 | Probably Damaging | 0.433 | Benign | 3.36 | Benign | 0.03 | Affected | 0.1348 | 0.1015 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2035T>C | F679L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (FoldX and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for F679L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.395 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.0 | -0.36 | Likely Benign | 0.36 | Likely Benign | 0.82 | Ambiguous | 0.506 | Likely Pathogenic | -5.91 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 3.54 | Benign | 0.03 | Affected | 0.1918 | 0.3493 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2037T>A | F679L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F679L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, FATHMM, and Foldetta, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. The majority of evidence points toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.395 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.0 | -0.36 | Likely Benign | 0.36 | Likely Benign | 0.82 | Ambiguous | 0.287 | Likely Benign | -5.91 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 3.54 | Benign | 0.03 | Affected | 0.1918 | 0.3493 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2037T>G | F679L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679L 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, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX and premPS are inconclusive. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.395 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.0 | -0.36 | Likely Benign | 0.36 | Likely Benign | 0.82 | Ambiguous | 0.287 | Likely Benign | -5.91 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 3.54 | Benign | 0.03 | Affected | 0.1918 | 0.3493 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2044T>C | Y682H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y682H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FATHMM, whereas the majority of other in silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict it to be pathogenic. The high‑accuracy consensus method SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized and the protein‑folding stability predictor Foldetta both return uncertain results, and FoldX and Rosetta individually are inconclusive. Overall, the preponderance of pathogenic predictions outweighs the benign ones, indicating that Y682H is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -9.255 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 1.78 | Ambiguous | 0.0 | 0.56 | Ambiguous | 1.17 | Ambiguous | 1.23 | Destabilizing | 0.399 | Likely Benign | -4.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.2405 | 0.0868 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.2060G>A | R687Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R687Q is annotated in ClinVar as benign (ClinVar ID 2693600.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, SGM‑Consensus indicating pathogenicity, and Foldetta (integrating FoldX‑MD and Rosetta outputs) classifying it as benign. With three high‑accuracy tools giving benign or uncertain results and only one (SGM‑Consensus) suggesting pathogenicity, the overall evidence leans toward a benign effect. This prediction aligns with the ClinVar benign classification, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | Likely Benign | 1 | -10.002 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.92 | Ambiguous | 0.1 | -0.37 | Likely Benign | 0.28 | Likely Benign | 1.55 | Destabilizing | 0.401 | Likely Benign | -3.37 | Deleterious | 1.000 | Probably Damaging | 0.844 | Possibly Damaging | 3.91 | Benign | 0.03 | Affected | 3.42 | 17 | 0.2143 | 0.1952 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||
| c.2080G>C | A694P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, while the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as Likely Pathogenic, with three of four votes pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for A694P. This conclusion is consistent with the absence of ClinVar annotation and gnomAD data, and there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -10.569 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.39 | Destabilizing | 0.2 | 5.59 | Destabilizing | 4.49 | Destabilizing | 0.82 | Ambiguous | 0.209 | Likely Benign | -2.77 | Deleterious | 0.988 | Probably Damaging | 0.578 | Possibly Damaging | 3.44 | Benign | 0.03 | Affected | 0.2265 | 0.3829 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2094G>C | E698D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E698D 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, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -6.716 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.16 | Likely Benign | 0.155 | Likely Benign | -2.45 | Neutral | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.35 | Benign | 0.03 | Affected | 0.1643 | 0.2597 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2094G>T | E698D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E698D 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, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -6.716 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.16 | Likely Benign | 0.155 | Likely Benign | -2.45 | Neutral | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.35 | Benign | 0.03 | Affected | 0.1643 | 0.2597 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2095G>A | V699M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V699M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441354‑G‑A). Across in silico predictors, benign calls are made by REVEL, Rosetta, Foldetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Default) are noted but not used as evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports benign stability. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the ClinVar uncertain status but provides a stronger leaning toward benignity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | Uncertain | 2 | 6-33441354-G-A | 8 | 4.96e-6 | -8.869 | Likely Pathogenic | 0.484 | Ambiguous | Likely Benign | -0.58 | Ambiguous | 0.1 | 0.29 | Likely Benign | -0.15 | Likely Benign | 0.96 | Ambiguous | 0.276 | Likely Benign | -2.18 | Neutral | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.37 | Benign | 0.03 | Affected | 3.47 | 10 | 0.0734 | 0.3071 | 2 | 1 | -2.3 | 32.06 | 257.8 | -47.2 | 0.0 | 0.0 | 0.9 | 0.1 | X | Potentially Benign | The isopropyl side chain of Val699, located on an α-helix (res. Leu685-Gln702), packs against hydrophobic residues (e.g., Leu703, Leu696, Leu435, Leu439) in the inter-helix space. In the variant simulations, the thioether side chain of Met699 has similar physicochemical properties to Val699 in the WT, and thus, it is able to maintain similar interactions. Consequently, the mutation causes no apparent changes in the structure. | ||||||||||||||
| c.2102C>A | P701H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P701H 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, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -8.786 | Likely Pathogenic | 0.553 | Ambiguous | Likely Benign | 1.40 | Ambiguous | 0.0 | -0.41 | Likely Benign | 0.50 | Ambiguous | 0.62 | Ambiguous | 0.141 | Likely Benign | -2.12 | Neutral | 0.936 | Possibly Damaging | 0.539 | Possibly Damaging | 3.38 | Benign | 0.03 | Affected | 0.1495 | 0.3495 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||
| c.2168C>T | T723I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723I is listed in ClinVar as Benign (ClinVar ID 436924.0) and is observed in gnomAD (variant ID 6‑33441633‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “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) also indicates a benign impact. 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 its ClinVar status. 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 | Likely Benign | 1 | 6-33441633-C-T | 2 | 1.24e-6 | -2.591 | Likely Benign | 0.120 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.0 | -0.20 | Likely Benign | -0.30 | Likely Benign | 0.26 | Likely Benign | 0.045 | Likely Benign | -2.09 | Neutral | 0.088 | Benign | 0.030 | Benign | 3.39 | Benign | 0.03 | Affected | 3.50 | 8 | 0.0708 | 0.5803 | 0 | -1 | 5.2 | 12.05 | 252.3 | -31.6 | 0.0 | 0.0 | -0.2 | 0.2 | X | Uncertain | The hydroxyl group of Thr723, located on the outer surface of an α-helix (res. Leu714-Arg726), continuously forms hydrogen bonds with the backbone carbonyl of Asn719 in the WT simulations, potentially lowering the stability of the α-helix. In the variant simulations, the sec-butyl side chain of Ile723 cannot form any hydrogen bonds, which, in theory, could increase the helix stability. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||||
| c.2177G>T | R726M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726M has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX is uncertain and is not counted as evidence. 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‑to‑2 split. Overall, the majority of tools and the two high‑accuracy methods predict a benign effect. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -8.611 | Likely Pathogenic | 0.750 | Likely Pathogenic | Likely Benign | 0.53 | Ambiguous | 0.1 | 0.31 | Likely Benign | 0.42 | Likely Benign | 0.20 | Likely Benign | 0.199 | Likely Benign | -2.02 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.1489 | 0.4051 | 0 | -1 | 6.4 | -24.99 | |||||||||||||||||||||||||||||||
| c.2179A>C | N727H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N727H 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, FoldX, Rosetta, Foldetta, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 as benign. Overall, the majority of predictions (six benign vs. five pathogenic) lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | -7.308 | In-Between | 0.224 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | -0.02 | Likely Benign | 0.06 | Likely Benign | 0.51 | Ambiguous | 0.171 | Likely Benign | -3.18 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.13 | Pathogenic | 0.03 | Affected | 0.1320 | 0.7186 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||
| c.2180A>T | N727I 2D 3DClick to see structure in 3D Viewer AISynGAP1 N727I is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta provide inconclusive results. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | -10.230 | Likely Pathogenic | 0.577 | Likely Pathogenic | Likely Benign | 0.17 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.43 | Likely Benign | 0.319 | Likely Benign | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.13 | Pathogenic | 0.03 | Affected | 0.0666 | 0.5917 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||
| c.2194A>G | R732G 2D AIThe SynGAP1 R732G missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33441659‑A‑G). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, while the most accurate single predictor (AlphaMissense‑Optimized) suggests a benign outcome. Given the lack of ClinVar evidence, there is no contradiction; the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | 6-33441659-A-G | 1 | 6.20e-7 | -9.348 | Likely Pathogenic | 0.295 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.98 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.56 | Benign | 0.03 | Affected | 3.59 | 7 | 0.3080 | 0.2942 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2197C>G | Q733E 2D AIThe SynGAP1 missense variant Q733E is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions from REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT; ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of ClinVar pathogenic reports. Thus, the variant is most likely benign, and this is not contradictory to ClinVar, which has no pathogenic classification. 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 | -7.651 | In-Between | 0.152 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.38 | Neutral | 0.983 | Probably Damaging | 0.637 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.1363 | 0.1130 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2218C>G | R740G 2D AIThe SynGAP1 missense variant R740G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the 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 | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | -4.556 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -2.55 | Deleterious | 0.993 | Probably Damaging | 0.887 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 0.3739 | 0.3149 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2219G>T | R740L 2D AIThe SynGAP1 missense variant R740L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | -4.958 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -2.30 | Neutral | 0.064 | Benign | 0.040 | Benign | 2.57 | Benign | 0.03 | Affected | 0.2341 | 0.4243 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2222C>T | P741L 2D AIThe SynGAP1 missense variant P741L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.850 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.63 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.84 | Benign | 0.03 | Affected | 0.1978 | 0.5780 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2225G>C | R742P 2D AIThe SynGAP1 missense variant R742P is catalogued in gnomAD (6-33441690‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. Only SIFT classifies the change as pathogenic, representing the sole discordant prediction. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise reports likely benign. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | 6-33441690-G-C | 1 | 6.20e-7 | -2.920 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.84 | Benign | 0.03 | Affected | 4.32 | 2 | 0.2598 | 0.3637 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.2246G>A | R749Q 2D AIThe SynGAP1 missense variant R749Q is listed in ClinVar (ID 793884.0) as Benign and is present in gnomAD (6‑33441711‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a Likely Benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence—including high‑accuracy predictions—supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441711-G-A | 4 | 2.48e-6 | -3.069 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.00 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 2 | 0.3467 | 0.2529 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2273A>G | Y758C 2D AIThe SynGAP1 missense variant Y758C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -5.256 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.921 | Probably Damaging | 2.71 | Benign | 0.03 | Affected | 0.3375 | 0.1922 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.2288T>A | L763H 2D AIThe SynGAP1 missense variant L763H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the predictions are mixed, with a slight tilt toward pathogenicity (5 pathogenic vs. 4 benign). Thus, the variant is most likely pathogenic according to the aggregate predictions, and this assessment does not contradict ClinVar, which currently has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -6.681 | Likely Benign | 0.640 | Likely Pathogenic | Likely Benign | 0.180 | Likely Benign | -0.79 | Neutral | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.36 | Pathogenic | 0.03 | Affected | 0.1021 | 0.0887 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2327G>C | G776A 2D AIThe SynGAP1 missense variant G776A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G776A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -5.275 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.82 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 4.26 | Benign | 0.03 | Affected | 0.3648 | 0.4971 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2348T>C | M783T 2D AIThe SynGAP1 missense variant M783T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the high‑accuracy consensus points to a benign effect, with no conflict with ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -4.064 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -2.08 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 2.69 | Benign | 0.03 | Affected | 0.2217 | 0.2308 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2360C>G | P787R 2D AIThe SynGAP1 missense variant P787R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, whereas the single high‑accuracy tool indicates benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.013 | Likely Benign | 0.784 | Likely Pathogenic | Likely Benign | 0.268 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.50 | Benign | 0.03 | Affected | 0.1373 | 0.2741 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2378A>C | K793T 2D AIThe SynGAP1 missense variant K793T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only SIFT predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) indicates likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for K793T, 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 | 0.971072 | Disordered | 0.426071 | Uncertain | 0.344 | 0.901 | 0.875 | -3.861 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.47 | Neutral | 0.174 | Benign | 0.123 | Benign | 4.12 | Benign | 0.03 | Affected | 0.2756 | 0.3473 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.2381C>T | P794L 2D AIThe SynGAP1 missense variant P794L is listed in ClinVar as Benign (ClinVar ID 859213.0) and is present in the gnomAD database (gnomAD ID 6‑33442933‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, while 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 P794L 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 | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | Benign/Likely benign | 2 | 6-33442933-C-T | 73 | 4.52e-5 | -3.808 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.80 | Neutral | 0.761 | Possibly Damaging | 0.321 | Benign | 4.24 | Benign | 0.03 | Affected | 4.07 | 3 | 0.2417 | 0.6733 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||
| c.2416T>A | F806I 2D AIThe SynGAP1 missense variant F806I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; Foldetta results are unavailable. Overall, the balance of evidence from the consensus of prediction algorithms points to a pathogenic impact for F806I. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -5.040 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | -3.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.15 | Pathogenic | 0.03 | Affected | 0.2583 | 0.1357 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2417T>A | F806Y 2D AIThe SynGAP1 missense variant F806Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also classifies it as benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign effect, 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. | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -5.229 | Likely Benign | 0.404 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -1.51 | Neutral | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 2.32 | Pathogenic | 0.03 | Affected | 0.1746 | 0.1437 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2431C>A | P811T 2D AIThe SynGAP1 missense variant P811T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for P811T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.329 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.94 | Neutral | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 2.77 | Benign | 0.03 | Affected | 0.1679 | 0.6095 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2444G>T | R815L 2D AISynGAP1 missense variant R815L is listed in ClinVar (ID 2505666.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools indicates a pathogenic effect, which contrasts with the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -8.546 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1817 | 0.5132 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.2447C>A | S816Y 2D AIThe SynGAP1 missense variant S816Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default, all of which classify the substitution as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, while Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.369 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.60 | Benign | 0.03 | Affected | 0.0668 | 0.4741 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2447C>T | S816F 2D AIThe SynGAP1 missense variant S816F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. When predictions are grouped, two tools predict benign and six predict pathogenic. High‑accuracy assessment further supports a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy predictors indicates that S816F is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.804 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.232 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.0605 | 0.5014 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2453C>G | P818R 2D AIThe SynGAP1 missense variant P818R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. ESM1b is uncertain and does not contribute to a consensus. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” designation. AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -7.267 | In-Between | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.374 | Likely Benign | -5.12 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 1.97 | Pathogenic | 0.03 | Affected | 0.1499 | 0.4547 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2456C>G | A819G 2D AIThe SynGAP1 missense variant A819G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs three pathogenic) support a benign classification. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.730 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.116 | Likely Benign | -2.17 | Neutral | 0.104 | Benign | 0.121 | Benign | 2.29 | Pathogenic | 0.03 | Affected | 0.2363 | 0.5396 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2461T>C | C821R 2D  AIThe SynGAP1 missense variant C821R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (six out of nine) indicate a pathogenic impact, while three suggest benign. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -3.997 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.183 | Likely Benign | -2.93 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.03 | Affected | 0.1944 | 0.1746 | -4 | -3 | -7.0 | 53.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2465C>T | T822M 2D  AIThe SynGAP1 missense variant T822M is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443017‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, 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. | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | 6-33443017-C-T | 5 | 3.10e-6 | -4.525 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | -2.11 | Neutral | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.48 | Pathogenic | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.6379 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||||||||||
| c.2496G>C | Q832H 2D AIThe SynGAP1 missense variant Q832H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point 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 | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -3.322 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.064 | Benign | 0.038 | Benign | 2.76 | Benign | 0.03 | Affected | 0.1263 | 0.3230 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2496G>T | Q832H 2D AIThe SynGAP1 missense variant Q832H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point 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 | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -3.322 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.064 | Benign | 0.038 | Benign | 2.76 | Benign | 0.03 | Affected | 0.1263 | 0.3230 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2507G>T | S836I 2D AIThe SynGAP1 missense variant S836I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows five tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, SIFT) predict pathogenicity. Two additional predictors (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessment further indicates a benign prediction from AlphaMissense‑Optimized; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (one benign, one pathogenic, two uncertain). Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar annotation. Therefore, 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. | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -7.751 | In-Between | 0.517 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -3.33 | Deleterious | 0.057 | Benign | 0.053 | Benign | 2.51 | Benign | 0.03 | Affected | 0.0756 | 0.5023 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2529G>A | M843I 2D AIThe SynGAP1 missense variant M843I is catalogued in gnomAD (6‑33443081‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with an equal number of benign and pathogenic calls; however, the majority of conventional tools lean toward benign, and the high‑accuracy consensus also favors benign. Thus, the variant is most likely benign based on current computational evidence, 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 | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | 6-33443081-G-A | 1 | 6.20e-7 | -6.219 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -1.97 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 2.66 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1497 | 0.3630 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.2529G>C | M843I 2D AIThe SynGAP1 missense variant M843I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -6.219 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -1.97 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 2.66 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1497 | 0.3630 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2529G>T | M843I 2D AIThe SynGAP1 missense variant M843I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -6.219 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -1.97 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 2.66 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1497 | 0.3630 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2542G>C | G848R 2D AIThe SynGAP1 missense variant G848R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G848R, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -4.867 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.05 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.0952 | 0.4251 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2560C>G | R854G 2D AIThe SynGAP1 missense variant R854G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign score, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.346 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -1.92 | Neutral | 0.980 | Probably Damaging | 0.818 | Possibly Damaging | 4.08 | Benign | 0.03 | Affected | 0.3469 | 0.3764 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2561G>C | R854P 2D AIThe SynGAP1 missense variant R854P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R854P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.627 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -1.02 | Neutral | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 4.06 | Benign | 0.03 | Affected | 0.2263 | 0.5163 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2561G>T | R854L 2D AIThe SynGAP1 missense variant R854L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R854L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.573 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -1.78 | Neutral | 0.960 | Probably Damaging | 0.765 | Possibly Damaging | 4.11 | Benign | 0.03 | Affected | 0.1875 | 0.5223 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2564T>G | L855R 2D AIThe SynGAP1 missense variant L855R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.485558 | Uncertain | 0.285 | 0.823 | 0.625 | -3.703 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.62 | Neutral | 0.026 | Benign | 0.015 | Benign | 4.00 | Benign | 0.03 | Affected | 0.1303 | 0.1187 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2575A>T | S859C 2D AIThe SynGAP1 missense variant S859C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The high‑accuracy consensus (SGM‑Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN reports the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -8.268 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.195 | Likely Benign | -2.01 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.94 | Benign | 0.03 | Affected | 0.1046 | 0.6153 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2585A>T | N862I 2D AIThe SynGAP1 missense variant N862I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default is uncertain. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority (2 pathogenic vs. 1 benign, 1 uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta results are unavailable. Overall, the majority of predictions support a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -8.702 | Likely Pathogenic | 0.561 | Ambiguous | Likely Benign | 0.195 | Likely Benign | -3.19 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 4.03 | Benign | 0.03 | Affected | 0.0844 | 0.6443 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.2630T>A | L877Q 2D AIThe SynGAP1 missense variant L877Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is Likely Benign, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -5.919 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -1.58 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.57 | Benign | 0.03 | Affected | 0.1208 | 0.0919 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2630T>C | L877P 2D  AIThe SynGAP1 missense variant L877P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -4.960 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.57 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.3899 | 0.1543 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2632A>T | T878S 2D AIThe SynGAP1 missense variant T878S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, 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 | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -2.493 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.06 | Neutral | 0.009 | Benign | 0.012 | Benign | 2.82 | Benign | 0.03 | Affected | 0.3557 | 0.4867 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2639C>A | A880D 2D AIThe SynGAP1 missense variant A880D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and no Foldetta stability result is available. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. 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 | -4.571 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.29 | Neutral | 0.918 | Possibly Damaging | 0.401 | Benign | 2.60 | Benign | 0.03 | Affected | 0.1664 | 0.1904 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2641T>A | L881M 2D AIThe SynGAP1 missense variant L881M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -4.419 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.31 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.49 | Pathogenic | 0.03 | Affected | 0.0807 | 0.3997 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2666G>T | G889V 2D AIThe SynGAP1 missense variant G889V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G889V, 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 | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | -5.781 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -2.11 | Neutral | 0.611 | Possibly Damaging | 0.243 | Benign | 2.39 | Pathogenic | 0.03 | Affected | 0.1198 | 0.4523 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2674T>A | S892T 2D AIThe SynGAP1 missense variant S892T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.806 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.09 | Neutral | 0.975 | Probably Damaging | 0.748 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 0.1606 | 0.5857 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2679G>C | Q893H 2D AIThe SynGAP1 missense variant Q893H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q893H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.783 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.1708 | 0.3879 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2679G>T | Q893H 2D AIThe SynGAP1 missense variant Q893H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q893H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.783 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.1708 | 0.3879 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2692T>G | S898A 2D AIThe SynGAP1 missense variant S898A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign classification. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence from both general and high‑accuracy predictors suggests that S898A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -3.932 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.98 | Neutral | 0.942 | Possibly Damaging | 0.748 | Possibly Damaging | 2.63 | Benign | 0.03 | Affected | 0.4552 | 0.5516 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2705C>G | A902G 2D AIThe SynGAP1 missense variant A902G is not listed in ClinVar and has no entry in gnomAD, indicating no reported clinical classification or population frequency data. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the consensus of available predictions points to a benign impact, with no conflict with ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -4.046 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -0.65 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.69 | Benign | 0.03 | Affected | 0.2177 | 0.4461 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2720G>T | S907I 2D AIThe SynGAP1 missense variant S907I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Likely Benign, and Foldetta results are unavailable. Based on the overall balance 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 | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -6.082 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -2.20 | Neutral | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 2.62 | Benign | 0.03 | Affected | 0.1006 | 0.5853 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2738C>G | T913R 2D  AIThe SynGAP1 missense variant T913R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus 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 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 | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -3.218 | Likely Benign | 0.494 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -0.97 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.68 | Benign | 0.03 | Affected | 0.1025 | 0.3373 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2752G>A | A918T 2D AISynGAP1 missense variant A918T is listed in ClinVar with an uncertain significance (ClinVar ID 3964538.0) and is present in gnomAD (6‑33443304‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 1 | 6-33443304-G-A | 1 | 6.20e-7 | -4.139 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.09 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1742 | 0.6430 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2753C>T | A918V 2D AIThe SynGAP1 missense variant A918V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443305‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability prediction is not available. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 3 | 6-33443305-C-T | 2 | 1.24e-6 | -3.684 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -1.61 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1226 | 0.5586 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.2756A>C | Q919P 2D AIThe SynGAP1 missense variant Q919P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -2.358 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.15 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.38 | Pathogenic | 0.03 | Affected | 0.2364 | 0.6108 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2757G>C | Q919H 2D AIThe SynGAP1 missense variant Q919H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.867 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -1.83 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.39 | Pathogenic | 0.03 | Affected | 0.1463 | 0.4203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2757G>T | Q919H 2D AIThe SynGAP1 missense variant Q919H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.867 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.83 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.39 | Pathogenic | 0.03 | Affected | 0.1463 | 0.4203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2794T>C | F932L 2D AIThe SynGAP1 missense variant F932L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the consensus of the available predictions points to a pathogenic effect for F932L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.989197 | Binding | 0.293 | 0.858 | 0.500 | -3.390 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.309 | Likely Benign | -3.50 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.36 | Pathogenic | 0.03 | Affected | 0.2373 | 0.3895 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2796C>A | F932L 2D AIThe SynGAP1 missense variant F932L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the consensus of the available predictions points to a pathogenic effect for F932L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.989197 | Binding | 0.293 | 0.858 | 0.500 | -3.390 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -3.50 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.36 | Pathogenic | 0.03 | Affected | 0.2373 | 0.3895 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2796C>G | F932L 2D AIThe SynGAP1 missense variant F932L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the consensus of the available predictions points to a pathogenic effect for F932L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.989197 | Binding | 0.293 | 0.858 | 0.500 | -3.390 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -3.50 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.36 | Pathogenic | 0.03 | Affected | 0.2373 | 0.3895 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2867C>G | S956C 2D AIThe SynGAP1 missense variant S956C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -9.292 | Likely Pathogenic | 0.108 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -0.34 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0.1833 | 0.5470 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2873A>T | H958L 2D AIThe SynGAP1 missense variant H958L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, SIFT and ESM1b, predict a pathogenic outcome. When the high‑accuracy consensus is considered, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely benign verdict, and AlphaMissense‑Optimized also reports benign. Foldetta predictions are unavailable. Overall, the majority of evidence supports a benign interpretation, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict existing ClinVar 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 | -8.422 | Likely Pathogenic | 0.087 | Likely Benign | Likely Benign | 0.181 | Likely Benign | -1.28 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.25 | Benign | 0.03 | Affected | 0.1723 | 0.5338 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2884C>T | H962Y 2D AIThe SynGAP1 missense variant H962Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H962Y, 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 | 0.984483 | Binding | 0.369 | 0.886 | 0.750 | -7.735 | In-Between | 0.167 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.878 | Possibly Damaging | 0.232 | Benign | 4.12 | Benign | 0.03 | Affected | 0.1741 | 0.4411 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2885A>T | H962L 2D AIThe SynGAP1 missense variant H962L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for H962L, 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 | 0.991070 | Disordered | 0.984483 | Binding | 0.369 | 0.886 | 0.750 | -8.478 | Likely Pathogenic | 0.108 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -1.49 | Neutral | 0.494 | Possibly Damaging | 0.170 | Benign | 4.15 | Benign | 0.03 | Affected | 0.1738 | 0.5487 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2914C>A | P972T 2D AIThe SynGAP1 missense variant P972T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -5.144 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.01 | Neutral | 0.078 | Benign | 0.042 | Benign | 4.29 | Benign | 0.03 | Affected | 0.1802 | 0.5726 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2968T>G | S990A 2D AIThe SynGAP1 missense variant S990A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -3.554 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.91 | Benign | 0.03 | Affected | 0.4537 | 0.4509 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2980A>C | K994Q 2D AIThe SynGAP1 missense variant K994Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -1.947 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.45 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.16 | Benign | 0.03 | Affected | 0.4975 | 0.1889 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2986C>A | P996T 2D AIThe SynGAP1 missense variant P996T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -5.138 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.71 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.26 | Benign | 0.03 | Affected | 0.1418 | 0.6163 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3020G>C | S1007T 2D AIThe SynGAP1 missense variant S1007T is reported in ClinVar as “Not submitted” (no ClinVar entry) and is present in gnomAD (allele ID 6‑33443572‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus as likely benign; Foldetta results are not available. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | 6-33443572-G-C | -4.719 | Likely Benign | 0.303 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.68 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1796 | 0.5550 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3023A>C | D1008A 2D AIThe SynGAP1 D1008A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | -3.210 | Likely Benign | 0.861 | Likely Pathogenic | Ambiguous | 0.209 | Likely Benign | -2.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.03 | Affected | 0.4014 | 0.6444 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3028T>G | F1010V 2D AIThe SynGAP1 missense variant F1010V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the balance of evidence from multiple independent predictors and the consensus analysis points to a benign classification for F1010V, with no conflict with ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -2.482 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.10 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.58 | Benign | 0.03 | Affected | 0.2351 | 0.2403 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>A | S1013Y 2D AIThe SynGAP1 missense variant S1013Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -4.882 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.78 | Neutral | 0.290 | Benign | 0.124 | Benign | 2.66 | Benign | 0.03 | Affected | 0.0954 | 0.5629 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>T | S1013F 2D AIThe SynGAP1 missense variant S1013F is catalogued in gnomAD (ID 6‑33443590‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen2_HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen2_HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to mixed signals, and Foldetta results are unavailable. Overall, the balance of evidence, including the benign call from AlphaMissense‑Optimized, points to a likely benign effect. This conclusion does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | 6-33443590-C-T | 1 | 6.20e-7 | -5.370 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -2.54 | Deleterious | 0.453 | Possibly Damaging | 0.272 | Benign | 2.65 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0922 | 0.5803 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3049T>G | F1017V 2D AIThe SynGAP1 missense variant F1017V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F1017V, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.517 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.97 | Deleterious | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1964 | 0.2137 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3061C>A | Q1021K 2D AIThe SynGAP1 missense variant Q1021K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a mixed signal: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Given the predominance of benign calls in the consensus and the lack of a ClinVar pathogenic annotation, the variant is most likely benign, with no conflict with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.276 | Likely Benign | 0.786 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -1.79 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.66 | Benign | 0.03 | Affected | 0.1551 | 0.4139 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3061C>G | Q1021E 2D AIThe SynGAP1 missense variant Q1021E is evaluated by multiple in silico tools. Benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The AlphaMissense‑Default tool gives an uncertain result. The consensus prediction from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus also indicates a likely benign effect. No Foldetta stability analysis is available for this residue. ClinVar contains no entry for this variant, and it is absent from gnomAD, so there is no external evidence to contradict the computational assessment. Based on the collective 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 | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.852 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.137 | Likely Benign | -1.21 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.65 | Benign | 0.03 | Affected | 0.1317 | 0.2069 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>G | Q1021R 2D AIThe SynGAP1 missense variant Q1021R is catalogued in gnomAD (ID 6‑33443614‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | 6-33443614-A-G | 1 | 6.20e-7 | -4.467 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | -1.80 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1257 | 0.2405 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||
| c.3071T>C | L1024P 2D AIThe SynGAP1 missense variant L1024P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard prediction tools lean toward pathogenicity, while high‑accuracy methods are inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.385 | Likely Benign | 0.730 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.974 | Probably Damaging | 2.43 | Pathogenic | 0.03 | Affected | 0.3187 | 0.2033 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3079A>T | N1027Y 2D AIThe SynGAP1 missense variant N1027Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.799 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.074 | Likely Benign | -2.15 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.0611 | 0.6133 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3095T>A | L1032Q 2D AIThe SynGAP1 missense variant L1032Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate evidence, 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.992 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.134 | Likely Benign | -0.78 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.03 | Affected | 0.1217 | 0.1677 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3100C>A | P1034T 2D AIThe SynGAP1 missense variant P1034T is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict a pathogenic outcome: SIFT and FATHMM. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions support a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.367 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -2.00 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0.1518 | 0.6620 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3106C>G | Q1036E 2D AIThe SynGAP1 missense variant Q1036E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains nine tools, while the pathogenic group contains one (SIFT). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable, so they do not influence the assessment. Overall, the evidence strongly suggests the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.797 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.22 | Neutral | 0.264 | Benign | 0.062 | Benign | 2.59 | Benign | 0.03 | Affected | 0.1629 | 0.3484 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3116T>G | I1039S 2D AIThe SynGAP1 missense variant I1039S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all classify the substitution as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. No Foldetta stability assessment is available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -1.688 | Likely Benign | 0.829 | Likely Pathogenic | Ambiguous | 0.171 | Likely Benign | -0.20 | Neutral | 0.032 | Benign | 0.008 | Benign | 2.76 | Benign | 0.03 | Affected | 0.2917 | 0.1294 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3122C>A | P1041H 2D AIThe SynGAP1 missense variant P1041H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta’s protein‑folding stability result is unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status because the variant has not been reported there. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -5.312 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.476 | Likely Benign | -3.32 | Deleterious | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 5.45 | Benign | 0.03 | Affected | 0.1883 | 0.5434 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3126G>C | Q1042H 2D AIThe SynGAP1 missense variant Q1042H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.258 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2207 | 0.4671 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3126G>T | Q1042H 2D AIThe SynGAP1 missense variant Q1042H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.258 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2207 | 0.4671 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3139T>C | S1047P 2D AIThe SynGAP1 missense variant S1047P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this does not contradict ClinVar status. 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 | -2.415 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.62 | Benign | 0.03 | Affected | 0.2373 | 0.5656 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3146C>G | P1049R 2D AIThe SynGAP1 missense variant P1049R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.144 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.90 | Neutral | 0.791 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.03 | Affected | 0.1376 | 0.3769 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3188G>T | G1063V 2D AIThe SynGAP1 missense variant G1063V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that G1063V is most likely benign, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -6.228 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.82 | Neutral | 0.004 | Benign | 0.002 | Benign | 4.29 | Benign | 0.03 | Affected | 0.1434 | 0.3707 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3228G>C | L1076F 2D AIThe SynGAP1 missense variant L1076F 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, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -4.606 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.03 | Affected | 0.0759 | 0.3767 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3228G>T | L1076F 2D AIThe SynGAP1 missense variant L1076F 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, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -4.606 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.03 | Affected | 0.0759 | 0.3767 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3230C>A | T1077K 2D AIThe SynGAP1 missense variant T1077K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the majority of evidence—including the SGM‑Consensus—suggests a benign impact, and this conclusion does not contradict the absence of a ClinVar entry. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.196 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.110 | Likely Benign | -1.44 | Neutral | 0.818 | Possibly Damaging | 0.460 | Possibly Damaging | 4.21 | Benign | 0.03 | Affected | 0.1176 | 0.3968 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>G | T1077R 2D AIThe SynGAP1 missense variant T1077R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), which collectively classify the variant as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and no Foldetta stability assessment is available. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.109 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.121 | Likely Benign | -1.01 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.18 | Benign | 0.03 | Affected | 0.1028 | 0.3491 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.323A>C | K108T 2D AIThe SynGAP1 missense variant K108T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. 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 | -2.941 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.48 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.08 | Benign | 0.03 | Affected | 0.2179 | 0.3538 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3246G>C | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.4779 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3246G>T | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is listed in gnomAD (ID 6‑33443798‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | 6-33443798-G-T | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.4779 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.324G>C | K108N 2D AISynGAP1 missense variant K108N is reported in gnomAD (6‑33432189‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign calls from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic calls from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta results are unavailable. Consequently, the evidence is evenly split, with no single prediction dominating. The variant is therefore not clearly benign or pathogenic based on current computational data, and this lack of consensus does not contradict any ClinVar classification, as none exists. 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 | 6-33432189-G-C | 1 | 6.20e-7 | -3.015 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.068 | Likely Benign | -1.35 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0.3904 | 0.1820 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||
| c.324G>T | K108N 2D AIThe SynGAP1 missense variant K108N is not reported in ClinVar and has no gnomAD entry. Consensus predictions from multiple in‑silico tools are split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which labels the variant as Likely Benign. Pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, the latter two high‑accuracy predictors both flagging the variant as Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not return a result for this variant, so its stability impact is unavailable. Overall, the majority of high‑confidence tools (AlphaMissense‑Optimized and the SGM‑Consensus) disagree, with AlphaMissense‑Optimized indicating pathogenicity while the consensus suggests benign. Because ClinVar contains no classification, there is no contradiction; the variant is most likely pathogenic based on the most reliable predictions. 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 | -3.015 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.068 | Likely Benign | -1.35 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0.3904 | 0.1820 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||
| c.3250C>T | P1084S 2D AIThe SynGAP1 missense variant P1084S is reported in gnomAD (variant ID 6‑33443802‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, 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 | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443802-C-T | 1 | 6.31e-7 | -3.987 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -2.24 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 4.03 | Benign | 0.03 | Affected | 3.77 | 5 | 0.3102 | 0.6215 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3260C>T | S1087F 2D AISynGAP1 missense variant S1087F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of reliable predictors and the two high‑accuracy tools suggest a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | Uncertain | 1 | -3.843 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -2.75 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0645 | 0.6029 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.3262A>G | S1088G 2D AIThe SynGAP1 missense variant S1088G is listed in ClinVar (ID 2742833.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | Uncertain | 1 | -5.034 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -1.83 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2541 | 0.5170 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3275T>G | L1092W 2D AIThe SynGAP1 missense variant L1092W is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta is unavailable. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus leans toward a benign interpretation. Thus, the variant is most likely benign based on the most reliable predictions, 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. | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -7.014 | In-Between | 0.804 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -2.00 | Neutral | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.58 | Benign | 0.03 | Affected | 0.0787 | 0.4033 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3278A>T | Q1093L 2D AIThe SynGAP1 missense variant Q1093L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -3.242 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.10 | Neutral | 0.224 | Benign | 0.091 | Benign | 2.72 | Benign | 0.03 | Affected | 0.0899 | 0.6837 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3284C>T | P1095L 2D AIThe SynGAP1 missense variant P1095L is catalogued in gnomAD (ID 6‑33443836‑C‑T) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta data are unavailable. 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. | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | 6-33443836-C-T | 1 | 6.44e-7 | -4.697 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -2.78 | Deleterious | 0.960 | Probably Damaging | 0.604 | Possibly Damaging | 2.74 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2199 | 0.6347 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.3287A>T | E1096V 2D AIThe SynGAP1 missense variant E1096V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence indicates 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.588 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | -1.06 | Neutral | 0.043 | Benign | 0.017 | Benign | 2.81 | Benign | 0.03 | Affected | 0.1082 | 0.7596 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3307C>G | R1103G 2D AIThe SynGAP1 missense variant R1103G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence—five benign predictions versus four pathogenic, with a benign high‑accuracy tool and no conflicting ClinVar annotation—suggests that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -3.516 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -2.65 | Deleterious | 0.911 | Possibly Damaging | 0.308 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0.3429 | 0.4077 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3318A>C | Q1106H 2D AIThe SynGAP1 missense variant Q1106H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.893 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1453 | 0.4214 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3318A>T | Q1106H 2D AIThe SynGAP1 missense variant Q1106H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.893 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1453 | 0.4214 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3340A>C | S1114R 2D AIThe SynGAP1 missense variant S1114R is 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, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence supports a benign classification, 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.037 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3342C>A | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3342C>G | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3349G>T | G1117C 2D AIThe SynGAP1 missense variant G1117C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -9.045 | Likely Pathogenic | 0.112 | Likely Benign | Likely Benign | 0.359 | Likely Benign | -1.30 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 4.56 | Benign | 0.03 | Affected | 0.1347 | 0.4612 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3358G>T | G1120C 2D AIThe SynGAP1 missense variant G1120C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for G1120C, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -9.324 | Likely Pathogenic | 0.112 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -1.32 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 3.60 | Benign | 0.03 | Affected | 0.1271 | 0.4227 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3377G>T | G1126V 2D AIThe SynGAP1 missense variant G1126V is listed in ClinVar with an uncertain significance and is present in the gnomAD database. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all classify the change as benign. Only the SIFT algorithm predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign, while Foldetta’s protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign variant, 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 | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | 6-33443929-G-T | -6.536 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.357 | Likely Benign | -1.20 | Neutral | 0.009 | Benign | 0.008 | Benign | 4.76 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1366 | 0.3884 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.3379G>T | G1127W 2D AIThe SynGAP1 missense variant G1127W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443931‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, indicates that 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. | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | 6-33443931-G-T | 3 | 2.01e-6 | -9.850 | Likely Pathogenic | 0.418 | Ambiguous | Likely Benign | 0.394 | Likely Benign | -1.36 | Neutral | 0.983 | Probably Damaging | 0.665 | Possibly Damaging | 4.79 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0782 | 0.4032 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.337G>A | G113R 2D AIThe SynGAP1 missense variant G113R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while AlphaMissense‑Optimized returns an uncertain result. The SGM‑Consensus, which aggregates 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 (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 annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.904 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.50 | Neutral | 0.267 | Benign | 0.080 | Benign | 4.16 | Benign | 0.03 | Affected | 0.1025 | 0.4138 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.337G>C | G113R 2D AIThe SynGAP1 missense variant G113R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely benign. Protein‑folding stability analysis via Foldetta is unavailable for this residue. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.904 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.088 | Likely Benign | -1.50 | Neutral | 0.267 | Benign | 0.080 | Benign | 4.16 | Benign | 0.03 | Affected | 0.1025 | 0.4138 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3407A>C | Q1136P 2D AIThe SynGAP1 missense variant Q1136P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.067 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.364 | Likely Benign | -1.06 | Neutral | 0.961 | Probably Damaging | 0.745 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2188 | 0.5344 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3408G>C | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3408G>T | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is reported in gnomAD (variant ID 6-33443960‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443960-G-T | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3413C>T | S1138F 2D AIThe SynGAP1 missense variant S1138F is not reported in ClinVar and is present in gnomAD (ID 6‑33444448‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The high‑accuracy AlphaMissense‑Optimized score is benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (pathogenic), resolves to 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 a benign effect. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | 6-33444448-C-T | 1 | 6.20e-7 | -6.298 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.407 | Likely Benign | -2.88 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0991 | 0.5623 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3435C>A | N1145K 2D AIThe SynGAP1 missense variant N1145K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, 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 | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3435C>G | N1145K 2D AIThe SynGAP1 missense variant N1145K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign impact. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3439A>G | T1147A 2D AIThe SynGAP1 missense variant T1147A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.115 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.60 | Neutral | 0.001 | Benign | 0.004 | Benign | 5.54 | Benign | 0.03 | Affected | 0.3816 | 0.3705 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3448G>A | A1150T 2D AIThe SynGAP1 missense variant A1150T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.467 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -2.06 | Neutral | 0.905 | Possibly Damaging | 0.687 | Possibly Damaging | 2.34 | Pathogenic | 0.03 | Affected | 0.1540 | 0.7182 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3454G>C | E1152Q 2D AIThe SynGAP1 missense variant E1152Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -2.798 | Likely Benign | 0.830 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -1.98 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.37 | Pathogenic | 0.03 | Affected | 0.1747 | 0.6395 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3520G>A | E1174K 2D AIThe SynGAP1 missense variant E1174K is listed in ClinVar with an uncertain significance (ClinVar ID 1905754.0) and is present in gnomAD (variant ID 6‑33444555‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, matching the reported SGM‑Consensus result. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Taken together, the majority of evidence points to 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 | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | Uncertain | 1 | 6-33444555-G-A | 2 | 1.24e-6 | -4.345 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.442 | Likely Benign | -1.59 | Neutral | 0.962 | Probably Damaging | 0.367 | Benign | 5.52 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1852 | 0.6521 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||
| c.3520G>C | E1174Q 2D AIThe SynGAP1 missense variant E1174Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta results are unavailable. Based on the overall distribution of predictions and the consensus from high‑accuracy tools, the variant is most likely benign. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -3.778 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.323 | Likely Benign | -1.04 | Neutral | 0.959 | Probably Damaging | 0.681 | Possibly Damaging | 5.43 | Benign | 0.03 | Affected | 0.0936 | 0.6268 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.352A>C | M118L 2D AIThe SynGAP1 missense variant M118L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for M118L, and this conclusion does not contradict any ClinVar status, as no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -1.319 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.09 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.11 | Benign | 0.03 | Affected | 0.1835 | 0.4511 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.352A>T | M118L 2D AIThe SynGAP1 missense variant M118L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT indicates a pathogenic effect, while the SGM‑Consensus (majority vote from 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 (derived from the four high‑accuracy tools) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for M118L, 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -1.319 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.09 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.11 | Benign | 0.03 | Affected | 0.1835 | 0.4511 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3530A>C | E1177A 2D AIThe SynGAP1 missense variant E1177A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome, reflecting the 3:1 benign majority among its constituents. 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 balance of evidence favors a benign effect for E1177A, and this conclusion does not conflict with ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.050 | Likely Benign | 0.774 | Likely Pathogenic | Likely Benign | 0.467 | Likely Benign | -2.12 | Neutral | 0.905 | Possibly Damaging | 0.373 | Benign | 5.50 | Benign | 0.03 | Affected | 0.2919 | 0.4369 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3532T>C | Y1178H 2D AIThe SynGAP1 missense variant Y1178H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as 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 balance 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. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -2.926 | Likely Benign | 0.775 | Likely Pathogenic | Likely Benign | 0.340 | Likely Benign | -0.78 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 5.48 | Benign | 0.03 | Affected | 0.2272 | 0.0341 | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||||||
| c.3560T>A | M1187K 2D AIThe SynGAP1 missense variant M1187K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 Pathogenic and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic based on current predictions. 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 | -3.712 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.594 | Likely Pathogenic | -0.71 | Neutral | 0.968 | Probably Damaging | 0.969 | Probably Damaging | 5.54 | Benign | 0.03 | Affected | 0.1758 | 0.0851 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3572G>T | R1191L 2D AIThe SynGAP1 missense variant R1191L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1191L. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | 0.014 | Likely Benign | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.352 | Likely Benign | -2.82 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 0.1792 | 0.4178 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3590A>T | E1197V 2D AIThe SynGAP1 missense variant E1197V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Overall, the balance of evidence (five pathogenic versus three benign predictions, with one uncertain) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -6.298 | Likely Benign | 0.923 | Likely Pathogenic | Ambiguous | 0.472 | Likely Benign | -3.28 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.40 | Benign | 0.03 | Affected | 0.0440 | 0.5320 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3601G>C | E1201Q 2D AIThe SynGAP1 E1201Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -4.415 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | -2.44 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.62 | Pathogenic | 0.03 | Affected | 0.0769 | 0.5473 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3606T>G | I1202M 2D  AIThe SynGAP1 I1202M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the majority of high‑accuracy predictions, the variant is most likely pathogenic. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for I1202M. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.529623 | Disordered | 0.510422 | Binding | 0.874 | 0.593 | 0.250 | -6.390 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.183 | Likely Benign | -2.21 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.82 | Pathogenic | 0.03 | Affected | 0.0684 | 0.2165 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3619G>C | E1207Q 2D AIThe SynGAP1 missense variant E1207Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta results are unavailable. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -6.789 | Likely Benign | 0.538 | Ambiguous | Likely Benign | 0.167 | Likely Benign | -1.95 | Neutral | 0.989 | Probably Damaging | 0.904 | Possibly Damaging | 2.11 | Pathogenic | 0.03 | Affected | 0.0808 | 0.4185 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.361G>C | A121P 2D AIThe SynGAP1 missense variant A121P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that A121P 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 | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.210 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.062 | Likely Benign | 0.95 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.03 | Affected | 0.2197 | 0.6196 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.362C>A | A121D 2D AIThe SynGAP1 missense variant A121D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this 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 | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.626 | Likely Benign | 0.595 | Likely Pathogenic | Likely Benign | 0.096 | Likely Benign | -0.89 | Neutral | 0.244 | Benign | 0.050 | Benign | 4.06 | Benign | 0.03 | Affected | 0.1876 | 0.1945 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3638A>T | N1213I 2D AIThe SynGAP1 missense variant N1213I is not reported in ClinVar and is absent from gnomAD. Prediction tools show a split opinion: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further highlight this discordance: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a pathogenic effect for N1213I, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | -10.798 | Likely Pathogenic | 0.743 | Likely Pathogenic | Likely Benign | 0.093 | Likely Benign | -3.10 | Deleterious | 0.996 | Probably Damaging | 0.930 | Probably Damaging | 2.71 | Benign | 0.03 | Affected | 0.0437 | 0.4407 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.365C>A | P122H 2D AIThe SynGAP1 missense variant P122H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for P122H. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -4.993 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -1.82 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2306 | 0.4213 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3664A>T | R1222W 2D AIThe SynGAP1 missense variant R1222W is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized yields an Uncertain result and Foldetta data are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1222W. This conclusion is not contradicted by ClinVar status, which currently contains no classification for the variant. 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 | -11.933 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | -6.00 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.03 | Affected | 0.0964 | 0.2761 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3684A>C | E1228D 2D AIThe SynGAP1 missense variant E1228D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification. 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 | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -4.788 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -1.89 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1667 | 0.2610 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3684A>T | E1228D 2D AIThe SynGAP1 missense variant E1228D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for E1228D, 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 | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -4.788 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -1.89 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1667 | 0.2610 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3688A>G | T1230A 2D AIThe SynGAP1 T1230A missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy tools—indicates that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.236 | Likely Benign | 0.644 | Likely Pathogenic | Likely Benign | 0.395 | Likely Benign | -2.10 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.58 | Benign | 0.03 | Affected | 0.2945 | 0.3231 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.368C>G | A123G 2D AIThe SynGAP1 missense variant A123G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -2.799 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.34 | Neutral | 0.421 | Benign | 0.074 | Benign | 4.13 | Benign | 0.03 | Affected | 0.2070 | 0.5039 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3697A>T | I1233F 2D AIThe SynGAP1 missense variant I1233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, more tools predict pathogenicity (five) than benignity (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -8.414 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -2.34 | Neutral | 0.968 | Probably Damaging | 0.713 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 0.0418 | 0.2731 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3700C>A | L1234M 2D AIThe SynGAP1 L1234M 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, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence slightly favors a pathogenic interpretation (5 pathogenic vs 4 benign predictions). This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.599170 | Disordered | 0.575096 | Binding | 0.844 | 0.527 | 0.125 | -8.235 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -0.99 | Neutral | 0.898 | Possibly Damaging | 0.354 | Benign | 1.50 | Pathogenic | 0.03 | Affected | 0.0648 | 0.2944 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.370G>C | A124P 2D AIThe SynGAP1 missense variant A124P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A124P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.030 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -1.19 | Neutral | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 4.05 | Benign | 0.03 | Affected | 0.2293 | 0.6141 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.371C>T | A124V 2D AIThe SynGAP1 A124V missense variant is listed in ClinVar (ID 1040523.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33432236‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 computational evidence indicates a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | Conflicting | 2 | 6-33432236-C-T | 9 | 5.58e-6 | -4.259 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -1.52 | Neutral | 0.173 | Benign | 0.009 | Benign | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0.1415 | 0.7433 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3748C>G | Q1250E 2D AIThe SynGAP1 missense variant Q1250E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for Q1250E, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -3.860 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.31 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.69 | Benign | 0.03 | Affected | 0.1281 | 0.1130 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3760G>C | E1254Q 2D AIThe SynGAP1 missense variant E1254Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—favors pathogenic (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -9.041 | Likely Pathogenic | 0.511 | Ambiguous | Likely Benign | 0.207 | Likely Benign | -2.18 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.35 | Pathogenic | 0.03 | Affected | 0.0768 | 0.5258 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3770C>A | S1257Y 2D AIThe SynGAP1 missense variant S1257Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans pathogenic (2 pathogenic vs 1 benign). Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.632 | Likely Pathogenic | 0.399 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -2.65 | Deleterious | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.55 | Benign | 0.03 | Affected | 0.0480 | 0.4463 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3775A>T | I1259F 2D AIThe SynGAP1 missense variant I1259F 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, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized returns an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of evidence (five pathogenic vs. three benign) points toward a pathogenic 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. | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -10.666 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.301 | Likely Benign | -1.68 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.55 | Benign | 0.03 | Affected | 0.0428 | 0.2563 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3824G>A | R1275Q 2D AIThe SynGAP1 missense variant R1275Q is listed in ClinVar with an uncertain significance (ClinVar ID 1720188.0) and is present in gnomAD (6‑33447872‑G‑A). Consensus from multiple in‑silico predictors shows a split: benign calls from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv and SIFT. High‑accuracy tools reinforce the benign trend: 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 majority of evidence points to a benign effect, 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 | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | Uncertain | 1 | 6-33447872-G-A | 2 | 1.29e-6 | -4.928 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.72 | Neutral | 0.898 | Possibly Damaging | 0.147 | Benign | 2.59 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2592 | 0.1336 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.383C>A | P128H 2D AIThe SynGAP1 missense variant P128H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -4.806 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.169 | Likely Benign | -1.90 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2207 | 0.3414 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3850C>A | L1284M 2D AIThe SynGAP1 missense variant L1284M is reported in gnomAD (ID 6‑33447898‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from the four benign‑oriented tools). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | 6-33447898-C-A | -5.332 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.49 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0731 | 0.2092 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3856G>C | E1286Q 2D AIThe SynGAP1 missense variant E1286Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.858 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -1.84 | Neutral | 0.872 | Possibly Damaging | 0.478 | Possibly Damaging | 2.47 | Pathogenic | 0.03 | Affected | 0.1185 | 0.4829 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3871C>A | L1291M 2D AIThe SynGAP1 missense variant L1291M is reported in gnomAD (ID 6‑33447919‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four benign predictors) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447919-C-A | -5.625 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.93 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.53 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0767 | 0.2973 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3874C>T | L1292F 2D AIThe SynGAP1 missense variant L1292F is reported in gnomAD (ID 6‑33447922‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. 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 | 6-33447922-C-T | -5.759 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.88 | Neutral | 0.611 | Possibly Damaging | 0.329 | Benign | 2.49 | Pathogenic | 0.03 | Affected | 3.77 | 5 | 0.0707 | 0.2799 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3886G>C | E1296Q 2D AIThe SynGAP1 missense variant E1296Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.510 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.148 | Likely Benign | -2.11 | Neutral | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.0978 | 0.5736 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>C | Q1298P 2D AIThe SynGAP1 missense variant Q1298P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -1.819 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -2.93 | Deleterious | 0.586 | Possibly Damaging | 0.105 | Benign | 2.76 | Benign | 0.03 | Affected | 0.2237 | 0.4025 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3894G>C | Q1298H 2D AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for Q1298H, 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3894G>T | Q1298H 2D AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments 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 consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.465 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.389A>C | Q130P 2D AIThe SynGAP1 missense variant Q130P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -0.659 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -0.10 | Neutral | 0.990 | Probably Damaging | 0.954 | Probably Damaging | 4.15 | Benign | 0.03 | Affected | 0.2414 | 0.4466 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3913A>C | T1305P 2D AIThe SynGAP1 missense variant T1305P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -1.882 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -1.41 | Neutral | 0.027 | Benign | 0.114 | Benign | 2.86 | Benign | 0.03 | Affected | 0.2157 | 0.5386 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>A | P1307Q 2D AIThe SynGAP1 missense variant P1307Q is listed in ClinVar (ID 982827.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451794‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | Uncertain | 1 | 6-33451794-C-A | -4.227 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.88 | Neutral | 0.988 | Probably Damaging | 0.765 | Possibly Damaging | 2.82 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1629 | 0.4464 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||
| c.3929C>G | T1310R 2D AIThe SynGAP1 missense variant T1310R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. Only SIFT predicts a damaging outcome, labeling it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Consequently, the aggregate evidence indicates that T1310R 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 | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -3.632 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -0.59 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.78 | Benign | 0.03 | Affected | 0.0844 | 0.2501 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3952C>A | L1318M 2D AIThe SynGAP1 missense variant L1318M is listed in gnomAD (ID 6‑33451826‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict 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 is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is available). 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-A | -4.625 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.62 | Neutral | 0.939 | Possibly Damaging | 0.396 | Benign | 4.01 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1083 | 0.4027 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3955G>A | A1319T 2D AIThe SynGAP1 missense variant A1319T is reported in gnomAD (variant ID 6‑33451829‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts a benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence supports a benign impact for A1319T, 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 | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-A | -4.861 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.917 | Possibly Damaging | 0.500 | Possibly Damaging | 4.13 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1944 | 0.7174 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3955G>C | A1319P 2D AIThe SynGAP1 missense variant A1319P is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33451829‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-C | 3 | 1.95e-6 | -2.783 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.81 | Neutral | 0.992 | Probably Damaging | 0.878 | Possibly Damaging | 4.06 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2360 | 0.5715 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.397C>A | L133M 2D AIThe SynGAP1 missense variant L133M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default; ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta results are unavailable. Overall, the majority of standard predictors (four pathogenic vs. three benign) indicate a pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -7.993 | In-Between | 0.841 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | -0.77 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.57 | Benign | 0.03 | Affected | 0.0856 | 0.2229 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.397C>G | L133V 2D AIThe SynGAP1 missense variant L133V is not 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes); Foldetta results are unavailable. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -8.429 | Likely Pathogenic | 0.848 | Likely Pathogenic | Ambiguous | 0.082 | Likely Benign | -1.27 | Neutral | 0.247 | Benign | 0.163 | Benign | 3.61 | Benign | 0.03 | Affected | 0.1561 | 0.1883 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3983G>A | R1328Q 2D AIThe SynGAP1 missense variant R1328Q is listed in ClinVar (ID 1805359.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451857‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | Uncertain | 3 | 6-33451857-G-A | 35 | 1.49e-4 | -2.921 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.799 | Possibly Damaging | 0.098 | Benign | 4.12 | Benign | 0.03 | Affected | 3.77 | 5 | 0.3503 | 0.1775 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3989A>C | Q1330P 2D AIThe SynGAP1 missense variant Q1330P is listed in gnomAD (ID 6‑33451863‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an “Uncertain” result, SGM‑Consensus confirms a benign leaning, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence favors 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 | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | 6-33451863-A-C | -3.087 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.076 | Likely Benign | -2.45 | Neutral | 0.898 | Possibly Damaging | 0.441 | Benign | 3.91 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2266 | 0.4983 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||
| c.3989A>G | Q1330R 2D AIThe SynGAP1 missense variant Q1330R is listed in gnomAD (ID 6‑33451863‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | 6-33451863-A-G | -3.601 | Likely Benign | 0.472 | Ambiguous | Likely Benign | 0.031 | Likely Benign | -1.65 | Neutral | 0.898 | Possibly Damaging | 0.341 | Benign | 3.95 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1349 | 0.2333 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||
| c.4021G>A | A1341T 2D AIThe SynGAP1 missense variant A1341T is listed in ClinVar (ID 837815) with an *Uncertain* clinical significance and is present in gnomAD (variant ID 6‑33451895‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus methods report a benign result: 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, did not provide a result for this variant. Overall, the majority of computational evidence indicates a benign effect, 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 | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | Conflicting | 4 | 6-33451895-G-A | 45 | 3.44e-5 | -3.224 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.58 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1835 | 0.7391 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.416G>T | S139I 2D AIThe SynGAP1 missense variant S139I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions come from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic effect. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -9.228 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -3.36 | Deleterious | 0.380 | Benign | 0.102 | Benign | 4.09 | Benign | 0.03 | Affected | 0.0948 | 0.4796 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.418T>A | S140T 2D AIThe SynGAP1 missense variant S140T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) remains Likely Benign. Foldetta predictions are unavailable. Overall, the balance of evidence, particularly the SGM‑Consensus and the majority of benign‑predicting tools, suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -6.336 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -1.94 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.59 | Benign | 0.03 | Affected | 0.1069 | 0.5722 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.421A>G | I141V 2D AIThe SynGAP1 I141V missense variant is catalogued in gnomAD (ID 6‑33432718‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM) and pathogenic (SIFT, AlphaMissense‑Default). The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the preponderance of evidence points to a benign effect, and this assessment aligns with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | 6-33432718-A-G | 1 | 6.42e-7 | -4.030 | Likely Benign | 0.785 | Likely Pathogenic | Ambiguous | 0.125 | Likely Benign | -0.58 | Neutral | 0.016 | Benign | 0.021 | Benign | 3.74 | Benign | 0.03 | Affected | 3.61 | 5 | 0.1101 | 0.3464 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.439C>A | Q147K 2D AIThe SynGAP1 missense variant Q147K is not 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -12.562 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.084 | Likely Benign | -2.12 | Neutral | 0.018 | Benign | 0.025 | Benign | 3.94 | Benign | 0.03 | Affected | 0.2012 | 0.3351 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||||||
| c.440A>T | Q147L 2D AIThe SynGAP1 missense variant Q147L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic interpretation, and this is not contradicted by any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -9.879 | Likely Pathogenic | 0.740 | Likely Pathogenic | Likely Benign | 0.185 | Likely Benign | -3.51 | Deleterious | 0.079 | Benign | 0.037 | Benign | 3.92 | Benign | 0.03 | Affected | 0.0861 | 0.4927 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.442C>G | P148A 2D AIThe SynGAP1 missense variant P148A is catalogued in gnomAD (ID 6‑33432739‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” because three of the four contributing tools predict benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. Thus, 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 | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | 6-33432739-C-G | 1 | 6.33e-7 | -6.890 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 4.00 | Benign | 0.03 | Affected | 3.61 | 5 | 0.3134 | 0.4123 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.457A>C | T153P 2D AIThe SynGAP1 missense variant T153P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign interpretation. This conclusion does not conflict with ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -7.092 | In-Between | 0.374 | Ambiguous | Likely Benign | 0.269 | Likely Benign | -1.67 | Neutral | 0.983 | Probably Damaging | 0.725 | Possibly Damaging | 4.09 | Benign | 0.03 | Affected | 0.2270 | 0.3660 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.473A>C | Q158P 2D AIThe SynGAP1 missense variant Q158P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q158P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.120 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.99 | Neutral | 0.851 | Possibly Damaging | 0.374 | Benign | 4.12 | Benign | 0.03 | Affected | 0.2167 | 0.4190 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.473A>T | Q158L 2D AIThe SynGAP1 missense variant Q158L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q158L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -5.965 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.652 | Possibly Damaging | 0.160 | Benign | 4.14 | Benign | 0.03 | Affected | 0.0711 | 0.4832 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.487T>A | F163I 2D AIThe SynGAP1 missense variant F163I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (five pathogenic vs. three benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -10.706 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -1.62 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 4.12 | Benign | 0.03 | Affected | 0.2114 | 0.2320 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.497C>G | A166G 2D AIThe SynGAP1 missense variant A166G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the 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 status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -8.188 | Likely Pathogenic | 0.215 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -1.16 | Neutral | 0.399 | Benign | 0.212 | Benign | 4.02 | Benign | 0.03 | Affected | 0.1665 | 0.3201 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.511G>A | A171T 2D AIThe SynGAP1 missense variant A171T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. This prediction does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -2.388 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.019 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.25 | Benign | 0.03 | Affected | 0.1075 | 0.5763 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.512C>T | A171V 2D AIThe SynGAP1 missense variant A171V is catalogued in gnomAD (ID 6‑33435154‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for A171V, 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 | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | 6-33435154-C-T | 1 | 6.20e-7 | -6.437 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.052 | Likely Benign | -1.65 | Neutral | 0.118 | Benign | 0.026 | Benign | 4.15 | Benign | 0.03 | Affected | 3.74 | 4 | 0.0766 | 0.4897 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.569G>T | S190I 2D AIThe SynGAP1 missense variant S190I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an Uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -9.868 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.316 | Likely Benign | -3.39 | Deleterious | 0.845 | Possibly Damaging | 0.368 | Benign | 4.03 | Benign | 0.03 | Affected | 0.0769 | 0.5963 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.571A>G | S191G 2D AIThe SynGAP1 missense variant S191G is not 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), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also leans toward benign (two benign versus two uncertain). 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 S191G is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.161 | In-Between | 0.506 | Ambiguous | Likely Benign | 0.173 | Likely Benign | -2.43 | Neutral | 0.131 | Benign | 0.058 | Benign | 3.77 | Benign | 0.03 | Affected | 0.2893 | 0.5335 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.572G>A | S191N 2D AIThe SynGAP1 missense variant S191N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools report an uncertain outcome: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign (2 benign vs. 1 pathogenic). AlphaMissense‑Optimized remains uncertain, and Foldetta folding‑stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for S191N, and this conclusion does not contradict any ClinVar annotation, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.887 | In-Between | 0.830 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | -2.21 | Neutral | 0.596 | Possibly Damaging | 0.260 | Benign | 3.78 | Benign | 0.03 | Affected | 0.1366 | 0.5898 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.572G>C | S191T 2D AIThe SynGAP1 missense variant S191T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of evidence supports a benign classification, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.315 | In-Between | 0.319 | Likely Benign | Likely Benign | 0.150 | Likely Benign | -2.34 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.81 | Benign | 0.03 | Affected | 0.1466 | 0.7405 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.601G>C | D201H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -8.595 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.68 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.06 | Ambiguous | 0.44 | Likely Benign | 0.284 | Likely Benign | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.04 | Benign | 0.03 | Affected | 0.1152 | 0.5838 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.604G>A | E202K 2D AIThe SynGAP1 E202K 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta’s stability assessment is uncertain. Overall, more tools (7 vs. 5) predict pathogenicity, and the high‑accuracy consensus leans toward pathogenic. Therefore, 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 | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -9.011 | Likely Pathogenic | 0.678 | Likely Pathogenic | Likely Benign | -0.24 | Likely Benign | 0.3 | -0.76 | Ambiguous | -0.50 | Ambiguous | 0.10 | Likely Benign | 0.231 | Likely Benign | -2.55 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 4.07 | Benign | 0.03 | Affected | 0.1963 | 0.6885 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.611C>A | S204Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive because it receives an equal split between pathogenic and benign calls. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -10.518 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 8.99 | Destabilizing | 3.8 | 5.20 | Destabilizing | 7.10 | Destabilizing | -0.03 | Likely Benign | 0.170 | Likely Benign | -0.96 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.0452 | 0.5625 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.611C>T | S204F 2D AIThe SynGAP1 missense variant S204F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and FATHMM, whereas a majority of tools (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with high‑accuracy tools supporting pathogenicity—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.693 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 7.35 | Destabilizing | 6.1 | 4.21 | Destabilizing | 5.78 | Destabilizing | -0.09 | Likely Benign | 0.161 | Likely Benign | -0.88 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.16 | Benign | 0.03 | Affected | 0.0468 | 0.5764 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.620A>T | K207M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact; premPS is uncertain. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.596 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.22 | Likely Benign | 0.0 | -0.47 | Likely Benign | -0.35 | Likely Benign | 0.59 | Ambiguous | 0.336 | Likely Benign | -4.67 | Deleterious | 0.985 | Probably Damaging | 0.832 | Possibly Damaging | 3.94 | Benign | 0.03 | Affected | 0.0982 | 0.4705 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.650A>T | E217V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217V 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 Rosetta, FATHMM, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E217V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -10.194 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.6 | 0.39 | Likely Benign | 0.58 | Ambiguous | 0.23 | Likely Benign | 0.723 | Likely Pathogenic | -4.84 | Deleterious | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 0.0919 | 0.8340 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.653T>G | F218C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33435295‑T‑G). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. Results that are uncertain or unavailable are FoldX, ESM1b, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic prediction (2 pathogenic vs. 1 benign votes); and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F218C, 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. | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | 6-33435295-T-G | 1 | 6.20e-7 | -7.234 | In-Between | 0.948 | Likely Pathogenic | Ambiguous | 1.49 | Ambiguous | 0.1 | 2.20 | Destabilizing | 1.85 | Ambiguous | 1.02 | Destabilizing | 0.744 | Likely Pathogenic | -4.92 | Deleterious | 0.994 | Probably Damaging | 0.667 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 3.41 | 13 | 0.2330 | 0.1321 | -2 | -4 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.677C>T | S226L 2D AIThe SynGAP1 missense variant S226L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -6.098 | Likely Benign | 0.239 | Likely Benign | Likely Benign | -0.12 | Likely Benign | 0.5 | -0.14 | Likely Benign | -0.13 | Likely Benign | 0.36 | Likely Benign | 0.578 | Likely Pathogenic | -3.87 | Deleterious | 0.437 | Benign | 0.048 | Benign | 5.73 | Benign | 0.03 | Affected | 0.1525 | 0.5907 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.688T>G | C230G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reached a consensus fall into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable and do not influence the overall assessment. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic; Foldetta remains uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -10.888 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.775 | Likely Pathogenic | -9.95 | Deleterious | 0.001 | Benign | 0.004 | Benign | 5.85 | Benign | 0.03 | Affected | 0.3313 | 0.2574 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.689G>T | C230F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and premPS give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that C230F is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -11.134 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | -0.09 | Likely Benign | 0.1 | -2.03 | Stabilizing | -1.06 | Ambiguous | 0.51 | Ambiguous | 0.840 | Likely Pathogenic | -8.73 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 5.96 | Benign | 0.03 | Affected | 0.1329 | 0.4173 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.697T>A | C233S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | 0.764 | Likely Pathogenic | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0.4528 | 0.2833 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.698G>C | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, 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 Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | 0.830 | Likely Pathogenic | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0.4528 | 0.2833 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.706G>A | A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -8.319 | Likely Pathogenic | 0.240 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.16 | Ambiguous | 0.83 | Ambiguous | 0.811 | Likely Pathogenic | -3.35 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 0.1342 | 0.6926 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.777 | Likely Pathogenic | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0.0913 | 0.5859 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | ||||||||||||||
| c.709G>C | A237P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, Foldetta is pathogenic, and AlphaMissense‑Optimized is uncertain (treated as unavailable). Overall, the preponderance of evidence indicates that A237P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -9.119 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.5 | 4.20 | Destabilizing | 2.15 | Destabilizing | 1.04 | Destabilizing | 0.752 | Likely Pathogenic | -3.68 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.77 | Benign | 0.03 | Affected | 0.1593 | 0.3724 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.716G>A | R239K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R239K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because uncertain or unavailable results are not taken as evidence for or against pathogenicity, the overall evidence still leans toward a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -12.492 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 1.93 | Ambiguous | 0.2 | 1.62 | Ambiguous | 1.78 | Ambiguous | 1.41 | Destabilizing | 0.719 | Likely Pathogenic | -2.52 | Deleterious | 0.882 | Possibly Damaging | 0.428 | Benign | 5.78 | Benign | 0.03 | Affected | 0.5222 | 0.4000 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||
| c.722A>C | K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.911 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 0.4 | 0.06 | Likely Benign | 1.03 | Ambiguous | 0.60 | Ambiguous | 0.853 | Likely Pathogenic | -5.14 | Deleterious | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 5.74 | Benign | 0.03 | Affected | 0.2021 | 0.3951 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.723A>C | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | 0.663 | Likely Pathogenic | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 0.3426 | 0.1872 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.723A>T | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | 0.663 | Likely Pathogenic | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 0.3426 | 0.1872 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.732G>C | E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D 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 and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -7.839 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.61 | Ambiguous | 1.04 | Ambiguous | 0.93 | Ambiguous | 0.730 | Likely Pathogenic | -2.53 | Deleterious | 0.976 | Probably Damaging | 0.675 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 0.1740 | 0.3783 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.732G>T | E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D 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 and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence points to a likely pathogenic effect for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -7.839 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.61 | Ambiguous | 1.04 | Ambiguous | 0.93 | Ambiguous | 0.730 | Likely Pathogenic | -2.53 | Deleterious | 0.976 | Probably Damaging | 0.675 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 0.1740 | 0.3783 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.739C>G | Q247E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247E is not 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, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are premPS, SIFT, and ESM1b. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign consensus (2 benign vs. 1 pathogenic, with the uncertain result treated as unavailable). High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign, Foldetta (combining FoldX‑MD and Rosetta outputs) is benign, and the SGM Consensus is benign. Overall, the collective 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. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -13.564 | Likely Pathogenic | 0.373 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.1 | -0.26 | Likely Benign | 0.08 | Likely Benign | 1.04 | Destabilizing | 0.474 | Likely Benign | -1.46 | Neutral | 0.128 | Benign | 0.039 | Benign | 5.80 | Benign | 0.03 | Affected | 0.1055 | 0.1476 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.743G>T | R248L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and FATHMM, whereas the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for R248L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -12.110 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.5 | 0.01 | Likely Benign | 0.57 | Ambiguous | 0.67 | Ambiguous | 0.825 | Likely Pathogenic | -6.06 | Deleterious | 0.979 | Probably Damaging | 0.680 | Possibly Damaging | 5.66 | Benign | 0.03 | Affected | 0.1616 | 0.4741 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.745G>C | A249P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is therefore pathogenic (3 pathogenic vs. 1 benign). High‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -10.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.76 | Destabilizing | 0.4 | 8.40 | Destabilizing | 5.58 | Destabilizing | 1.04 | Destabilizing | 0.756 | Likely Pathogenic | -3.32 | Deleterious | 0.176 | Benign | 0.039 | Benign | 5.57 | Benign | 0.03 | Affected | 0.1429 | 0.3537 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.746C>T | A249V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A249V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, no high‑accuracy tool provides a definitive pathogenic or benign verdict. Overall, the majority of available predictions (seven pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -9.417 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 1.48 | Ambiguous | 0.6 | 0.51 | Ambiguous | 1.00 | Ambiguous | 0.41 | Likely Benign | 0.652 | Likely Pathogenic | -2.47 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.76 | Benign | 0.03 | Affected | 0.0737 | 0.4677 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.754C>G | P252A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P252A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from FATHMM, and a majority of pathogenic calls from 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). Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P252A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.587 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.97 | Ambiguous | 0.1 | 1.74 | Ambiguous | 1.36 | Ambiguous | 0.69 | Ambiguous | 0.831 | Likely Pathogenic | -7.35 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 5.87 | Benign | 0.03 | Affected | 0.3490 | 0.4161 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.759C>A | N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K resides in the PH domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM. In contrast, the majority of predictors—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)—label it pathogenic or likely pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. This assessment is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.759C>G | N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools fall into two groups: benign predictions come from FoldX, FATHMM, premPS, and Foldetta, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of tools predict pathogenicity, and the two most reliable predictors also lean pathogenic, whereas only one high‑accuracy tool suggests benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.766A>G | N256D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N256D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX is uncertain and therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the overall consensus leans toward a pathogenic effect, with 10 tools supporting pathogenicity versus 4 supporting benignity. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -12.478 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.3 | 0.21 | Likely Benign | 0.45 | Likely Benign | 0.44 | Likely Benign | 0.701 | Likely Pathogenic | -4.36 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.81 | Benign | 0.03 | Affected | 0.1890 | 0.3514 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.787G>A | V263M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. No conflicting evidence is present. **Based on the aggregate 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 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -5.956 | Likely Benign | 0.218 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | -0.24 | Likely Benign | -0.02 | Likely Benign | 0.43 | Likely Benign | 0.444 | Likely Benign | -0.95 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.84 | Benign | 0.03 | Affected | 0.0665 | 0.3545 | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||||||
| c.795G>C | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, whereas the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | 0.350 | Likely Benign | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 0.3691 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.795G>T | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, while the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results are reported only for FoldX, Foldetta, and premPS, and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | 0.351 | Likely Benign | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 0.3691 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.799T>G | W267G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -15.020 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.2 | 3.99 | Destabilizing | 4.20 | Destabilizing | 1.20 | Destabilizing | 0.678 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.96 | Pathogenic | 0.03 | Affected | 0.4049 | 0.1481 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.802A>C | I268L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268L is not 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools give uncertain results: premPS and AlphaMissense‑Default. 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 indicates a benign folding‑stability outcome. 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. | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -6.544 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.15 | Likely Benign | 0.96 | Ambiguous | 0.390 | Likely Benign | -1.84 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.65 | Pathogenic | 0.03 | Affected | 0.0635 | 0.3037 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.808G>C | E270Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270Q missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS, whereas the majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates several high‑accuracy predictors, classifies the variant as Likely Pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is Uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Rosetta alone is Uncertain, and Foldetta’s uncertainty reflects limited stability change evidence. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -11.096 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.50 | Ambiguous | 0.46 | Likely Benign | 0.418 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.65 | Pathogenic | 0.03 | Affected | 0.1044 | 0.4015 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.811G>T | A271S 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A271S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for A271S, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | Uncertain | 1 | -9.552 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 0.19 | Likely Benign | 0.1 | 1.47 | Ambiguous | 0.83 | Ambiguous | 1.14 | Destabilizing | 0.453 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.64 | Pathogenic | 0.03 | Affected | 0.2260 | 0.3312 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||
| c.815G>A | R272Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R272Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437720‑G‑A). Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and PROVEAN. Those that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; and Foldetta predicts benign. With the majority of high‑accuracy tools supporting a benign effect, the variant is most likely benign, which does not contradict its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | Uncertain | 2 | 6-33437720-G-A | 14 | 8.67e-6 | -9.559 | Likely Pathogenic | 0.286 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.15 | Likely Benign | 0.44 | Likely Benign | 1.00 | Destabilizing | 0.321 | Likely Benign | -1.81 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.88 | Pathogenic | 0.03 | Affected | 3.38 | 19 | 0.2966 | 0.1973 | 1 | 1 | 1.0 | -28.06 | 255.7 | 52.9 | 0.0 | 0.0 | -0.2 | 0.1 | X | Uncertain | The guanidinium group of Arg272, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), is stably maintained in an upright and outward position via stacking with the indole ring of the Trp362 side chain in another β strand (res. Thr359-Pro364). In the WT simulations, Arg272 forms hydrogen bonds with the glycine-rich Ω loop residues (res. Val365-Pro398, e.g., Gly380) and creates a salt bridge with the carboxylate group of the Asp304 side chain.In the variant simulations, the carboxamide group of the Gln272 side chain does not stack with the indole ring of Trp362 as stably as the guanidinium group of Arg272 in the WT. Consequently, the Gln272 side chain is freer to interact with the loop residues than Arg272, potentially negatively affecting the dynamic SynGAP-membrane association. Additionally, Arg272 faces the RasGTPase interface, so the residue swap could impact the SynGAP-Ras complex formation and GTPase activation. | ||||||||||||||
| c.823C>T | P275S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑T). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for P275S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-T | 1 | 6.20e-7 | -7.886 | In-Between | 0.312 | Likely Benign | Likely Benign | 2.11 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.70 | Ambiguous | 0.77 | Ambiguous | 0.388 | Likely Benign | -5.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.78 | Pathogenic | 0.03 | Affected | 3.38 | 19 | 0.3489 | 0.3339 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.826C>A | P276T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, two pathogenic), and Foldetta is uncertain. Overall, the majority of tools (six pathogenic vs. four benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | -5.793 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 2.61 | Destabilizing | 0.1 | 0.75 | Ambiguous | 1.68 | Ambiguous | 0.63 | Ambiguous | 0.293 | Likely Benign | -3.53 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 1.87 | Pathogenic | 0.03 | Affected | 0.1601 | 0.4676 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.831G>C | K277N 2D AIThe SynGAP1 missense variant K277N is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and premPS. Tools that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Benign. No predictions are missing or inconclusive. Overall, the majority of tools (10/14) predict pathogenicity, whereas four tools predict benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | -9.646 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.07 | Likely Benign | 0.4 | 0.08 | Likely Benign | 0.01 | Likely Benign | 0.46 | Likely Benign | 0.572 | Likely Pathogenic | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.03 | Affected | 0.3265 | 0.0568 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.831G>T | K277N 2D AIThe SynGAP1 missense variant K277N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely pathogenic; Foldetta, a protein‑folding stability predictor, reports a benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to a pathogenic classification. 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 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | -9.646 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.07 | Likely Benign | 0.4 | 0.08 | Likely Benign | 0.01 | Likely Benign | 0.46 | Likely Benign | 0.572 | Likely Pathogenic | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.03 | Affected | 0.3265 | 0.0568 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.836G>T | R279L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R279L is reported in gnomAD (ID 6‑33437741‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-T | 1 | 6.20e-7 | -12.390 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.01 | Likely Benign | 0.2 | 0.14 | Likely Benign | 0.08 | Likely Benign | 0.39 | Likely Benign | 0.576 | Likely Pathogenic | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.91 | Pathogenic | 0.03 | Affected | 3.39 | 18 | 0.1682 | 0.3266 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||
| c.844T>A | C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the majority of other in‑silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, and Foldetta) return uncertain results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | Uncertain | 1 | -11.846 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.1 | 1.23 | Ambiguous | 1.39 | Ambiguous | 1.62 | Destabilizing | 0.460 | Likely Benign | -9.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.64 | Pathogenic | 0.03 | Affected | 3.39 | 18 | 0.5009 | 0.1286 | Weaken | 0 | -1 | -3.3 | -16.06 | 233.2 | 14.8 | -0.1 | 0.0 | -0.2 | 0.3 | X | Potentially Benign | The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element. | |||||||||||||||
| c.845G>C | C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -11.846 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.1 | 1.23 | Ambiguous | 1.39 | Ambiguous | 1.62 | Destabilizing | 0.436 | Likely Benign | -9.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.64 | Pathogenic | 0.03 | Affected | 3.39 | 18 | 0.5009 | 0.1286 | Weaken | 0 | -1 | -3.3 | -16.06 | 233.2 | 14.8 | -0.1 | 0.0 | -0.2 | 0.3 | X | Potentially Benign | The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element. | |||||||||||||||||
| c.846T>G | C282W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C282W is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated predictors—FoldX, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. Uncertain results come only from premPS and Rosetta, which are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic status; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. **Thus, the variant is most likely pathogenic based on the collective predictions, 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 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -15.392 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 10.69 | Destabilizing | 1.7 | -1.05 | Ambiguous | 4.82 | Destabilizing | 0.70 | Ambiguous | 0.418 | Likely Benign | -10.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.03 | Affected | 0.1457 | 0.2978 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.850C>G | L284V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284V missense variant has no ClinVar entry and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, AlphaMissense‑Default, and Foldetta. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the balance of evidence leans toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -6.726 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 1.65 | Ambiguous | 0.2 | 2.08 | Destabilizing | 1.87 | Ambiguous | 1.38 | Destabilizing | 0.248 | Likely Benign | -2.32 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.18 | Pathogenic | 0.03 | Affected | 0.1259 | 0.2456 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.869T>C | L290P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously favor a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. No tool in the dataset predicts a benign outcome; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -11.796 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.1 | 1.10 | Ambiguous | 0.95 | Ambiguous | 0.56 | Ambiguous | 0.727 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.01 | Pathogenic | 0.03 | Affected | 0.3646 | 0.1703 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.874G>T | A292S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292S 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 and FoldX, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. No prediction or folding‑stability result is missing; uncertain outcomes are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -8.514 | Likely Pathogenic | 0.804 | Likely Pathogenic | Ambiguous | 0.40 | Likely Benign | 0.2 | 2.13 | Destabilizing | 1.27 | Ambiguous | 0.70 | Ambiguous | 0.364 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.69 | Pathogenic | 0.03 | Affected | 0.2850 | 0.6389 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.875C>T | A292V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -11.170 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.04 | Destabilizing | 0.5 | 4.60 | Destabilizing | 3.32 | Destabilizing | 0.85 | Ambiguous | 0.430 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1272 | 0.6253 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.880A>G | T294A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294A missense variant is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain call is FoldX. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic, and Foldetta predicts Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -12.371 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.87 | Ambiguous | 0.1 | 2.27 | Destabilizing | 2.07 | Destabilizing | 1.05 | Destabilizing | 0.719 | Likely Pathogenic | -4.60 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | -0.18 | Pathogenic | 0.03 | Affected | 0.3687 | 0.3494 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.880A>T | T294S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). In silico predictors that classify the variant as benign are absent; all available tools that provide a definitive call predict a deleterious effect. Pathogenic predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of pathogenic calls and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no opposing evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -7.785 | In-Between | 0.954 | Likely Pathogenic | Ambiguous | 1.12 | Ambiguous | 0.2 | 1.70 | Ambiguous | 1.41 | Ambiguous | 1.19 | Destabilizing | 0.613 | Likely Pathogenic | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 0.08 | Pathogenic | 0.03 | Affected | 0.2983 | 0.3396 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.881C>G | T294S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T294S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). In silico predictors that classify the variant as benign are absent; all available tools that provide a definitive call predict a deleterious effect. Pathogenic predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of pathogenic calls and the SGM Consensus support a pathogenic classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which contains no opposing evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -7.785 | In-Between | 0.954 | Likely Pathogenic | Ambiguous | 1.12 | Ambiguous | 0.2 | 1.70 | Ambiguous | 1.41 | Ambiguous | 1.19 | Destabilizing | 0.583 | Likely Pathogenic | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 0.08 | Pathogenic | 0.03 | Affected | 0.2983 | 0.3396 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>A | T295N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295N 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, ESM1b, and Foldetta, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -6.588 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.24 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.45 | Likely Benign | 0.89 | Ambiguous | 0.438 | Likely Benign | -3.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | 0.1522 | 0.4457 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.910G>A | D304N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D304N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. 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. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | Uncertain | 1 | -6.194 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.30 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | 0.345 | Likely Benign | -4.18 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.81 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 0.1353 | 0.7205 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.933C>A | H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. The high‑accuracy consensus methods give mixed signals: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, more tools (seven) predict pathogenicity than benign (four), and the SGM Consensus supports a pathogenic classification, while Foldetta offers a contrary benign prediction. The variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -8.656 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.27 | Likely Benign | 0.92 | Ambiguous | 0.414 | Likely Benign | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0.1490 | 0.3775 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.933C>G | H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q 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, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With seven pathogenic versus four benign predictions, the overall consensus leans toward pathogenicity. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -8.656 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.27 | Likely Benign | 0.92 | Ambiguous | 0.414 | Likely Benign | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0.1490 | 0.3775 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.947A>T | N316I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and premPS, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction is missing or inconclusive beyond the uncertain AlphaMissense‑Optimized result. Based on the preponderance of pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -11.164 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 2.74 | Destabilizing | 0.2 | 4.10 | Destabilizing | 3.42 | Destabilizing | 0.18 | Likely Benign | 0.318 | Likely Benign | -6.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.03 | Affected | 0.0734 | 0.7422 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.949C>G | L317V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L317V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign calls come from REVEL and AlphaMissense‑Optimized, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, SGM‑Consensus predicting Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an Uncertain result. Overall, the majority of evidence points toward pathogenicity, with only two tools indicating benign. Because ClinVar contains no entry, there is no conflict with existing clinical interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -8.406 | Likely Pathogenic | 0.403 | Ambiguous | Likely Benign | 2.51 | Destabilizing | 0.1 | 0.97 | Ambiguous | 1.74 | Ambiguous | 1.12 | Destabilizing | 0.298 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.03 | Affected | 0.1518 | 0.2950 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.952C>T | P318S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P318S is present in gnomAD (variant ID 6‑33437857‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a deleterious effect. Pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Taken together, the overwhelming majority of evidence supports a pathogenic classification, and this conclusion is consistent with the absence of a ClinVar record rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.111485 | Structured | 0.400936 | Uncertain | 0.858 | 0.234 | 0.000 | 6-33437857-C-T | 1 | 6.19e-7 | -9.954 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 2.22 | Destabilizing | 0.1 | 1.71 | Ambiguous | 1.97 | Ambiguous | 1.00 | Destabilizing | 0.626 | Likely Pathogenic | -7.05 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.87 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 0.3692 | 0.5653 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||
| c.953C>T | P318L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P318L is listed in ClinVar with an uncertain significance (ClinVar ID 956570.0) and is present in gnomAD (6‑33437858‑C‑T). Functional prediction tools that agree on a benign effect are Rosetta and premPS. The remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for P318L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.111485 | Structured | 0.400936 | Uncertain | 0.858 | 0.234 | 0.000 | Uncertain | 3 | 6-33437858-C-T | 3 | 1.86e-6 | -10.090 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.33 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.80 | Ambiguous | 0.43 | Likely Benign | 0.624 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 0.2166 | 0.6941 | -3 | -3 | 5.4 | 16.04 | 228.6 | -68.9 | -0.7 | 0.7 | -0.4 | 0.1 | X | Potentially Benign | The cyclic five-membered pyrrolidine ring of Pro318, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Asp330-Ala322, res. Thr305-Asn315), packs against the hydrophobic side chain of Ile205 at the end of the anti-parallel β sheet in the PH domain. In the variant simulations, the iso-butyl side chain of Leu318 is unable to do the same, potentially weakening the PH and C2 domain association. Importantly, the residue swap could also affect loop formation during folding, as proline can make tighter turns than leucine. Because the residue swap could affect the C2 domain stability, it could also negatively impact the SynGAP-membrane association. | |||||||||||||
| c.962G>C | R321P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8/12) predict pathogenicity, whereas 4/12 predict benign, with two high‑accuracy tools supporting benign and one supporting pathogenic. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict 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 | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -11.576 | Likely Pathogenic | 0.740 | Likely Pathogenic | Likely Benign | 1.22 | Ambiguous | 0.3 | -0.77 | Ambiguous | 0.23 | Likely Benign | 0.41 | Likely Benign | 0.488 | Likely Benign | -3.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.2186 | 0.3661 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.962G>T | R321L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; FoldX and Rosetta individually are inconclusive. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -11.709 | Likely Pathogenic | 0.551 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.0 | -0.58 | Ambiguous | -0.02 | Likely Benign | 0.18 | Likely Benign | 0.451 | Likely Benign | -4.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | 0.1745 | 0.4048 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.967C>A | L323M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L323M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Foldetta, premPS, AlphaMissense‑Default, ESM1b, and Rosetta—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Taken together, the evidence leans toward a benign impact for the variant, and this assessment 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. | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | -7.065 | In-Between | 0.427 | Ambiguous | Likely Benign | 0.11 | Likely Benign | 0.1 | 1.82 | Ambiguous | 0.97 | Ambiguous | 0.93 | Ambiguous | 0.270 | Likely Benign | -1.02 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 0.64 | Pathogenic | 0.03 | Affected | 0.0637 | 0.3010 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.977A>C | H326P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions are absent; pathogenic predictions are reported by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). The only inconclusive result is premPS, which is listed as Uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -18.452 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.3 | 2.59 | Destabilizing | 2.63 | Destabilizing | 0.88 | Ambiguous | 0.711 | Likely Pathogenic | -8.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.2383 | 0.4492 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.995A>T | D332V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332V 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, Foldetta, and premPS, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results come from FoldX, Rosetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -13.710 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 1.39 | Ambiguous | 0.1 | -0.52 | Ambiguous | 0.44 | Likely Benign | 0.50 | Likely Benign | 0.484 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.21 | Pathogenic | 0.03 | Affected | 0.0573 | 0.4132 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.998A>T | K333I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K333I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta give uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -14.517 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.0 | 0.95 | Ambiguous | 0.63 | Ambiguous | 0.43 | Likely Benign | 0.544 | Likely Pathogenic | -6.49 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.89 | Pathogenic | 0.03 | Affected | 0.0931 | 0.3521 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1004G>T | R335L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R335L is not listed in ClinVar (ClinVar ID None) and has no reported allele in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, and premPS. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX are uncertain and are treated as unavailable for pathogenicity inference. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of predictions (8 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | -13.226 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.0 | -0.19 | Likely Benign | 0.16 | Likely Benign | 0.40 | Likely Benign | 0.196 | Likely Benign | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.73 | Pathogenic | 0.04 | Affected | 0.1382 | 0.4753 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1015A>C | K339Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evaluated tools (8 pathogenic vs. 4 benign) indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -10.952 | Likely Pathogenic | 0.863 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.0 | -0.50 | Ambiguous | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.458 | Likely Benign | -3.06 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 1.90 | Pathogenic | 0.04 | Affected | 0.4041 | 0.1012 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1025A>C | Y342S 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant Y342S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). Uncertain results come from premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods specifically give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | Uncertain | 2 | -7.996 | In-Between | 0.925 | Likely Pathogenic | Ambiguous | 3.03 | Destabilizing | 0.1 | 2.87 | Destabilizing | 2.95 | Destabilizing | 0.93 | Ambiguous | 0.407 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.75 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.4617 | 0.2637 | -3 | -2 | 0.5 | -76.10 | 200.1 | 77.8 | 0.0 | 0.0 | -0.2 | 0.1 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. In the WT simulations, the phenol ring of Tyr342 contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Ser342 side chain cannot participate in the stack formation. Instead, the hydroxyl group of the Ser342 side chain forms a hydrogen bond with the imidazole ring of His326 in a neighboring β strand (res. Ala322-Asp330). This disrupts the formation of a hydrogen bond between His326 and the carboxylate group of the Glu283 side chain from another β strand (res. Arg279-Cys285). Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association, as the hydroxyl group of Ser342 could form hydrogen bonds with membrane-facing loop residues. However, this phenomenon cannot be addressed using solvent-only simulations. | |||||||||||||||||
| c.1030G>A | G344S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344S is listed in ClinVar (ID 981240.0) as Pathogenic and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic; the only inconclusive result is premPS, which is marked Uncertain. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | Pathogenic | 5 | -11.254 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 9.02 | Destabilizing | 0.7 | 6.08 | Destabilizing | 7.55 | Destabilizing | 0.98 | Ambiguous | 0.790 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.45 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.2735 | 0.5324 | 1 | 0 | -0.4 | 30.03 | 217.3 | -51.7 | 0.0 | 0.1 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Because Gly344 lacks a proper side chain, it allows the anti-parallel β sheet strand (res. Gly341-Pro349) to have a slight twist. Within a β strand, side chains normally alternate between outward and inward positions, but glycine is an exception as it allows the alternating pattern to skip a residue. Introducing serine or any other residue with a side chain at position 344 prevents this unique skip in the alternating pattern, causing structural strain or likely preventing correct folding altogether. Additionally, Tyr342 shields Gly344 from the solvent, contributing to twist formation in the β sheet and stabilizing the β-strand.In the variant simulations, the side chain of Ser344 assumes the inward position. However, the hydrophobic niche formed by multiple C2 domain residues (e.g., Val365, Val343, Leu327) is not accommodating for its hydroxyl group. The outward position, not seen in the simulations, would be equally disadvantageous due to the presence of hydrophobic residues on that side as well (e.g., Leu345, Tyr342). Serine is also not well-suited for twist formation, as it tends to suppress twisting and bending in β sheets. At this position, the hydroxyl group of Ser344 could also form hydrogen bonds with the backbone atoms of the Gly-rich Ω loop in the C2 domain (e.g., Thr366, Leu367, Gly378; res. Pro364-Pro398), potentially adversely affecting membrane-loop dynamics and ultimately compromising the stability of the SynGAP-membrane association. | |||||||||||||||
| c.1034T>G | L345R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L345R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic prediction. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -10.325 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.66 | Ambiguous | 1.31 | Ambiguous | 1.28 | Destabilizing | 0.247 | Likely Benign | -3.98 | Deleterious | 0.993 | Probably Damaging | 0.796 | Possibly Damaging | 1.81 | Pathogenic | 0.04 | Affected | 0.1140 | 0.0685 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1052C>G | A351G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A351G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic), and Foldetta is uncertain. Taken together, the majority of available predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.983 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.72 | Ambiguous | 0.55 | Ambiguous | 0.041 | Likely Benign | -2.53 | Deleterious | 0.688 | Possibly Damaging | 0.138 | Benign | 1.77 | Pathogenic | 0.04 | Affected | 0.2298 | 0.4737 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1060G>C | A354P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A354P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are FoldX, SIFT, and FATHMM. Predictions that are inconclusive are Foldetta, premPS, and Rosetta. 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 pathogenic. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | Uncertain | 1 | -5.971 | Likely Benign | 0.239 | Likely Benign | Likely Benign | 2.66 | Destabilizing | 0.2 | 1.55 | Ambiguous | 2.11 | Destabilizing | 0.57 | Ambiguous | 0.241 | Likely Benign | -1.66 | Neutral | 0.001 | Benign | 0.002 | Benign | 1.76 | Pathogenic | 0.04 | Affected | 0.2259 | 0.5884 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||
| c.1064G>A | G355E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355E is catalogued in gnomAD (6‑33437969‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. Overall, the preponderance of evidence from standard pathogenicity predictors points to a deleterious effect, and this conclusion is not contradicted by any ClinVar classification (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | 6-33437969-G-A | 2 | 1.24e-6 | -9.395 | Likely Pathogenic | 0.891 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.6 | 0.63 | Ambiguous | 0.68 | Ambiguous | 0.54 | Ambiguous | 0.349 | Likely Benign | -6.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.04 | Affected | 3.38 | 24 | 0.1590 | 0.4271 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||
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