Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | |||||||||||||||||||||||||||||||||
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| Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | 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.453C>A | D151E 2D  AIThe SynGAP1 D151E variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. 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) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.662 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -2.02 | Neutral | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 3.99 | Benign | 0.11 | Tolerated | 3.61 | 5 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.3653A>T | E1218V 2D  AISynGAP1 missense variant E1218V is listed in ClinVar with an uncertain significance (ClinVar ID 1015602.0) and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. When the high‑accuracy consensus is considered, 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 change. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Uncertain | 2 | -5.647 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -5.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1136C>T | S379L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379L is listed in ClinVar as Benign (ClinVar ID 1360860.0) and is present in gnomAD (ID 6‑33438041‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta and SIFT. Foldetta and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification; there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Benign | 1 | 6-33438041-C-T | 8 | 4.05e-5 | -5.641 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.469 | Likely Benign | 0.39 | Likely Benign | 0.2 | 3.38 | Destabilizing | 1.89 | Ambiguous | -0.52 | Ambiguous | -0.85 | Neutral | 0.015 | Benign | 0.002 | Benign | 3.83 | Benign | 0.04 | Affected | 4.32 | 11 | -3 | -2 | 4.6 | 26.08 | 251.9 | -48.1 | 0.6 | 1.1 | 0.0 | 0.5 | Uncertain | Ser379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.2393C>T | P798L 2D  AIThe SynGAP1 missense variant P798L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442945‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; a Foldetta stability prediction is not available. 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 | SH3-binding motif | Uncertain | 2 | 6-33442945-C-T | 6 | 3.72e-6 | -5.640 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.86 | Neutral | 0.981 | Probably Damaging | 0.631 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||
| c.2948G>A | S983N 2D  AISynGAP1 missense variant S983N is listed as Benign in ClinVar (ID 469153) and is present in gnomAD (6‑33443500‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; Foldetta results are not available. Overall, the majority of available predictions (five pathogenic vs. three benign) suggest a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 1 | 6-33443500-G-A | 6 | 3.72e-6 | -5.604 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -1.78 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||
| c.3962C>A | P1321Q 2D  AIThe SynGAP1 missense variant P1321Q is listed in ClinVar (ID 833687.0) as benign and is present in gnomAD (variant ID 6‑33451836‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑confidence SGM consensus and AlphaMissense‑Optimized—supports a benign impact. This conclusion aligns with the ClinVar benign status, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33451836-C-A | 1 | 6.58e-7 | -5.594 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.74 | Neutral | 0.659 | Possibly Damaging | 0.034 | Benign | 4.24 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||
| c.2713C>T | R905C 2D  AIThe SynGAP1 missense variant R905C (ClinVar ID 469152.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443265‑C‑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. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic impact, whereas the high‑accuracy AlphaMissense‑Optimized tool suggests a benign effect. Consequently, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 2 | 6-33443265-C-T | 15 | 9.31e-6 | -5.578 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 2.57 | Benign | 0.01 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.1040C>A | T347N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347N is listed in ClinVar with an uncertain significance (ClinVar ID 3672484.0) and is present in the gnomAD database (gnomAD ID 6‑33437945‑C‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the collective evidence points to a benign effect, aligning with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33437945-C-A | 9 | 5.58e-6 | -5.545 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.41 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.44 | Likely Benign | -0.06 | Likely Benign | 1.96 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.67 | Pathogenic | 0.60 | Tolerated | 3.37 | 25 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||
| c.3977C>T | P1326L 2D AIThe SynGAP1 missense variant P1326L is listed in ClinVar (ID 1004879.0) 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, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. 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 (FoldX‑MD/ Rosetta) stability result is available for this variant. Overall, the majority of evidence—including the high‑confidence SGM consensus and AlphaMissense‑Optimized prediction—supports a benign classification, which does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.541 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.06 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.401G>A | S134N 2D AIThe SynGAP1 missense variant S134N is listed in ClinVar with an “Uncertain” status (ClinVar ID 2819575.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The remaining tools—AlphaMissense‑Optimized and the SGM‑Consensus—are inconclusive; the consensus score is “Likely Benign” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the balance of evidence points to a benign impact, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.534 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -1.62 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.90 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.3662G>A | R1221Q 2D  AIThe SynGAP1 missense variant R1221Q is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446654‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, SGM Consensus is likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Conflicting | 2 | 6-33446654-G-A | 4 | 2.48e-6 | -5.491 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.46 | Neutral | 0.836 | Possibly Damaging | 0.153 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||
| c.3197C>T | P1066L 2D AIThe SynGAP1 missense variant P1066L is listed in ClinVar as a benign variant (ClinVar ID 951518.0) and is present in gnomAD (ID 6‑33443749‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33443749-C-T | 14 | 8.71e-6 | -5.478 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -3.68 | Deleterious | 0.996 | Probably Damaging | 0.903 | Possibly Damaging | 2.72 | Benign | 0.00 | Affected | 4.32 | 2 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.2818G>A | G940S 2D  AIThe SynGAP1 missense variant G940S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443370‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443370-G-A | 1 | 6.20e-7 | -5.451 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.45 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.77 | Benign | 0.44 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.3970C>T | P1324S 2D  AIThe SynGAP1 missense variant P1324S is listed in ClinVar as Benign (ClinVar ID 1137951.0) and is present in gnomAD (ID 6‑33451844‑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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, which is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33451844-C-T | 5 | 3.26e-6 | -5.451 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.35 | Neutral | 0.225 | Benign | 0.092 | Benign | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
| c.1153T>C | S385P 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant S385P is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438058‑T‑C). Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions from FoldX and Rosetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438058-T-C | -5.431 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.385 | Likely Benign | 0.91 | Ambiguous | 0.6 | -0.90 | Ambiguous | 0.01 | Likely Benign | 0.19 | Likely Benign | -0.26 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.63 | Benign | 0.04 | Affected | 4.32 | 3 | 1 | -1 | -0.8 | 10.04 | 210.3 | 18.5 | 1.8 | 0.9 | 0.3 | 0.0 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Pro385 is potentially tolerated in the Ω loop. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||
| c.3638A>C | N1213T 2D  AIThe SynGAP1 missense variant N1213T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446630‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||
| c.3977C>A | P1326Q 2D AIThe SynGAP1 missense variant P1326Q is listed in ClinVar (ID 2806103.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33451851‑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 “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33451851-C-A | 1 | 6.40e-7 | -5.422 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.86 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | -1.9 | 31.01 | |||||||||||||||||||||||||||
| c.2207G>A | R736H 2D  AIThe SynGAP1 missense variant R736H is listed in ClinVar (ID 1351080.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441672‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign. Foldetta results are not available. Overall, the majority of computational evidence indicates a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33441672-G-A | 6 | 3.72e-6 | -5.409 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.12 | Neutral | 0.004 | Benign | 0.001 | Benign | 2.50 | Benign | 0.00 | Affected | 4.07 | 3 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.227C>G | S76C 2D  AIThe SynGAP1 missense variant S76C is listed in ClinVar with an “Uncertain” status (ClinVar ID 1951273.0) and is present in the gnomAD database (gnomAD ID 6‑33425835‑C‑G). 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, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33425835-C-G | 2 | 1.24e-6 | -5.408 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.78 | Neutral | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 3.71 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||
| c.3G>A | M1I 2D  AIThe SynGAP1 missense variant M1I is listed in ClinVar (ID 833646.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM all classify the substitution as benign, while SIFT uniquely predicts it to be pathogenic. The consensus score from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy predictors are incomplete: AlphaMissense‑Optimized and the Foldetta stability assessment are unavailable for this variant. Taking the collective evidence into account, the variant is most likely benign, 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 | Conflicting | 3 | -5.397 | Likely Benign | 0.227 | Likely Benign | -0.17 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.25 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
| c.2681G>A | G894E 2D  AIThe SynGAP1 missense variant G894E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443233‑G‑A). 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. AlphaMissense‑Optimized is reported as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta (FoldX‑MD/Rosetta) result is available. Overall, the majority of predictions support a benign impact, and this is consistent with the ClinVar “Uncertain” classification; thus the variant is most likely benign and does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443233-G-A | 6 | 3.72e-6 | -5.377 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -2.07 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.68 | Benign | 0.01 | Affected | 4.32 | 4 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||
| 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 | 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 | -2 | 0 | 0.7 | 32.06 | |||||||||||||||||||||||||||||||
| c.1312G>A | A438T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33438217‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status of “Uncertain.” Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Conflicting | 3 | 6-33438217-G-A | 16 | 9.91e-6 | -5.339 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.021 | Likely Benign | 0.21 | Likely Benign | 0.0 | -0.07 | Likely Benign | 0.07 | Likely Benign | 0.36 | Likely Benign | -0.81 | Neutral | 0.300 | Benign | 0.011 | Benign | 4.18 | Benign | 0.14 | Tolerated | 3.38 | 26 | 1 | 0 | -2.5 | 30.03 | 214.2 | -42.7 | -0.3 | 0.1 | -0.4 | 0.1 | X | Potentially Benign | The methyl group of Ala438, located in a four-residue loop connecting two α helices (res. Asn440-Thr458 and Pro413-Glu436), packs against hydrophobic residues from a nearby α helix or loop residues (e.g., Leu703, Val699). In the variant simulations, the methyl group of Thr438 is able to establish similar hydrophobic packing. Moreover, the hydroxyl group also H-bonds with nearby residues, such as the carbonyl group of the neighboring loop residue Pro437. Accordingly, the residue swap does not generate an apparent negative effect on the protein structure based on the simulations. | ||||||||
| c.3326T>C | L1109P 2D  AIThe SynGAP1 missense variant L1109P is listed in ClinVar with an uncertain significance (ClinVar ID 1730257.0) and is not reported in gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | -5.313 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -0.52 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.65 | Benign | 0.07 | Tolerated | 4.32 | 2 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.1729G>A | A577T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A577T is listed in ClinVar as benign (ClinVar ID 2195056.0) and is present in gnomAD (ID 6‑33440781‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other high‑confidence stability predictions are available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Benign | 1 | 6-33440781-G-A | 6 | 3.72e-6 | -5.311 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.427 | Likely Benign | 0.86 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.70 | Ambiguous | 0.54 | Ambiguous | -1.47 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.47 | Tolerated | 3.37 | 34 | 1 | 0 | -2.5 | 30.03 | 191.9 | -43.4 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. In the variant simulations, the hydroxyl group of the Thr577 side chain hydrogen bonds with the backbone atoms of Arg573 and Lys574 within the same helix, which has the potential to weaken the stability of the secondary structure element. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | ||||||||
| c.2830G>A | G944S 2D AIThe SynGAP1 missense variant G944S is listed in ClinVar as a benign alteration (ClinVar ID 833552.0) and is present in the gnomAD database (gnomAD ID 6‑33443382‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available for this variant. Overall, the majority of computational evidence supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33443382-G-A | 13 | 8.05e-6 | -5.303 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.75 | Neutral | 0.007 | Benign | 0.004 | Benign | 3.77 | Benign | 0.00 | Affected | 4.32 | 4 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.3160G>A | G1054S 2D AIThe SynGAP1 missense variant G1054S is listed in ClinVar (ID 699126.0) as Benign and is present in gnomAD (variant ID 6‑33443712‑G‑A). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33443712-G-A | 32 | 1.99e-5 | -5.294 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.21 | Neutral | 0.121 | Benign | 0.013 | Benign | 4.04 | Benign | 0.63 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.1964T>A | L655Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655Q is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for L655Q, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -5.278 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.69 | Ambiguous | 0.34 | Likely Benign | -0.15 | Likely Benign | 0.61 | Neutral | 0.955 | Possibly Damaging | 0.602 | Possibly Damaging | 3.59 | Benign | 0.65 | Tolerated | 3.39 | 24 | -2 | -2 | -7.3 | 14.97 | 229.9 | -8.6 | 0.0 | 0.0 | 0.4 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu655, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Gln655 dynamically interacts with neighboring residues (e.g., Glu651, Glu656, Arg544) on the protein surface, with no negative structural effects. | |||||||||||
| c.2195G>A | R732K 2D  AIThe SynGAP1 missense variant R732K is listed in ClinVar (ID 537019.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33441660‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this consensus does not conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33441660-G-A | 4 | 2.48e-6 | -5.278 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.82 | Neutral | 0.973 | Probably Damaging | 0.943 | Probably Damaging | 2.69 | Benign | 0.21 | Tolerated | 3.59 | 7 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||
| c.2812G>A | G938R 2D  AIThe SynGAP1 missense variant G938R is listed in ClinVar (ID 1019898.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus three pathogenic predictions) supports a benign classification. This consensus does not contradict the ClinVar “Uncertain” designation, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.3980C>T | P1327L 2D AIThe SynGAP1 missense variant P1327L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33451854‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a benign outcome. Foldetta results are not available for this variant. Overall, the majority of computational evidence supports a benign classification, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33451854-C-T | 2 | 1.28e-6 | -5.264 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.24 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.12 | Benign | 0.10 | Tolerated | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.3821G>A | R1274H 2D AIThe SynGAP1 missense variant R1274H (ClinVar ID 2803246.0) is classified as Benign in ClinVar and is present in gnomAD (ID 6‑33447869‑G‑A). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. No Foldetta stability prediction is available for this residue. Overall, the majority of conventional tools predict pathogenicity, and the high‑accuracy AlphaMissense‑Optimized result is benign, leaving the evidence mixed. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, contradicting its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 1 | 6-33447869-G-A | 4 | 2.58e-6 | -5.259 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -3.20 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
| c.3974C>T | P1325L 2D AIThe SynGAP1 missense variant P1325L is listed in ClinVar (ID 1720534.0) with an uncertain significance designation and is present in gnomAD (variant ID 6‑33451848‑C‑T). Functional 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1325L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33451848-C-T | -5.256 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -1.05 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.2835T>A | H945Q 2D  AIThe SynGAP1 missense variant H945Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443387‑T‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, and the SGM consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—is also benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign impact, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443387-T-A | 3 | 1.86e-6 | -5.248 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.343 | Likely Benign | -0.36 | Neutral | 0.995 | Probably Damaging | 0.939 | Probably Damaging | 5.03 | Benign | 0.06 | Tolerated | 4.32 | 4 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||
| c.1150G>A | G384S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G384S (gnomAD ID 6-33438055‑G‑A) is listed in ClinVar with an uncertain significance. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX or Rosetta alone is available. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438055-G-A | 1 | 6.22e-7 | -5.243 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.315 | Likely Benign | 1.92 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.79 | Ambiguous | 0.19 | Likely Benign | -0.67 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 1.33 | Pathogenic | 0.04 | Affected | 4.32 | 2 | 1 | 0 | -0.4 | 30.03 | 202.4 | -49.8 | 0.5 | 1.0 | -0.2 | 0.0 | Uncertain | Gly384 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycines, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Ser384 is potentially tolerated in the Ω loop, although the hydroxyl group of Ser384 forms various hydrogen bonds with several other loop residues in the variant simulations. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.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 | 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 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||
| c.2912C>A | P971H 2D  AIThe SynGAP1 missense variant P971H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443464‑C‑A). 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 | Uncertain | 1 | 6-33443464-C-A | 1 | 6.20e-7 | -5.243 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -1.11 | Neutral | 0.898 | Possibly Damaging | 0.477 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 4.32 | 2 | -2 | 0 | -1.6 | 40.02 | |||||||||||||||||||||||||||
| c.1195G>A | A399T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A399T is listed in ClinVar (ID 1990638.0) as Benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the variant is most likely benign, and this conclusion aligns with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Benign | 1 | -5.236 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.272 | Likely Benign | 1.24 | Ambiguous | 0.1 | 0.91 | Ambiguous | 1.08 | Ambiguous | 0.49 | Likely Benign | -0.40 | Neutral | 0.131 | Benign | 0.039 | Benign | 5.41 | Benign | 0.69 | Tolerated | 3.38 | 26 | 1 | 0 | -2.5 | 30.03 | 211.4 | -41.4 | 0.0 | 0.0 | 0.6 | 0.4 | X | Potentially Pathogenic | The methyl group of Ala399, located in an anti-parallel β sheet strand (res. Ala399-Ile411), is swapped for a hydroxyl-containing threonine. In the variant simulations, the hydroxyl group of Thr399 can form H-bonds with the backbone atoms of the residues in the membrane-facing loops (e.g., Gly382) in the C2 domain. Consequently, the ability of the Thr399 side chain to form H-bonds with the membrane-facing loops could adversely affect the dynamics and stability of the SynGAP-membrane association. However, since the effects on the dynamics of the membrane-facing loops can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||
| c.182A>C | E61A 2D  AIThe SynGAP1 missense variant E61A is listed in ClinVar (ID 3767543.0) 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while 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 current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.235 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -1.52 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||
| c.958G>A | V320I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta remains inconclusive. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence points to a benign effect for V320I, and this conclusion does not conflict with the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | -5.220 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -0.27 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.20 | Likely Benign | 0.01 | Likely Benign | -0.21 | Neutral | 0.198 | Benign | 0.114 | Benign | 1.77 | Pathogenic | 0.45 | Tolerated | 3.38 | 23 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||
| c.2219G>A | R740Q 2D AIThe SynGAP1 missense variant R740Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441684‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so it does not influence the assessment. Overall, the majority of predictions indicate that R740Q is most likely benign, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33441684-G-A | 4 | 2.48e-6 | -5.195 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.67 | Neutral | 0.999 | Probably Damaging | 0.881 | Possibly Damaging | 2.60 | Benign | 0.08 | Tolerated | 4.32 | 2 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.3056G>T | R1019L 2D  AIThe SynGAP1 missense variant R1019L is listed in ClinVar with an “Uncertain” status (ClinVar ID 3364537.0) and is present in gnomAD (gnomAD ID 6‑33443608‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) remains pathogenic. 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 pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Uncertain | 1 | 6-33443608-G-T | 2 | 1.24e-6 | -5.194 | Likely Benign | 0.752 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -3.57 | Deleterious | 0.800 | Possibly Damaging | 0.573 | Possibly Damaging | 2.40 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||
| c.3172G>A | G1058S 2D AIThe SynGAP1 missense variant G1058S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33443724-G-A). 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 classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33443724-G-A | 114 | 7.08e-5 | -5.178 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.26 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.38 | Benign | 0.04 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.221G>A | S74N 2D AIThe SynGAP1 missense variant S74N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33425829‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability result is available. Overall, the majority of computational evidence indicates that the variant is most likely benign, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33425829-G-A | 5 | 3.10e-6 | -5.156 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.89 | Neutral | 0.043 | Benign | 0.007 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.3233T>A | V1078D 2D  AIThe SynGAP1 missense variant V1078D is listed in ClinVar (ID 2993122.0) 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), ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default, AlphaMissense‑Optimized, 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 pathogenic, SGM‑Consensus as likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the ClinVar “Uncertain” designation; there is no contradiction with the existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.155 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.158 | Likely Benign | -1.45 | Neutral | 0.003 | Benign | 0.008 | Benign | 3.84 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | -2 | -7.7 | 15.96 | ||||||||||||||||||||||||||||||
| c.1339G>C | V447L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||
| c.3223C>A | Q1075K 2D  AIThe SynGAP1 missense variant Q1075K (ClinVar ID 2762879.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” because three of the four contributing tools predict benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.135 | Likely Benign | 0.728 | Likely Pathogenic | Likely Benign | 0.134 | Likely Benign | -0.67 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 2.75 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||
| c.73C>T | R25W 2D  AIThe SynGAP1 missense variant R25W is listed in ClinVar with an “Uncertain” status (ClinVar ID 2993054.0) and is present in gnomAD (ID 6‑33423482‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33423482-C-T | 6 | 3.72e-6 | -5.133 | Likely Benign | 0.549 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -1.60 | Neutral | 0.994 | Probably Damaging | 0.919 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||
| c.3293G>A | S1098N 2D AIThe SynGAP1 missense variant S1098N is listed in ClinVar (ID 864704.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443845‑G‑A). All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443845-G-A | 6 | 3.89e-6 | -5.120 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.58 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.76 | Benign | 0.36 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.3304G>C | A1102P 2D  AIThe SynGAP1 missense variant A1102P is listed in ClinVar (ID 2789225.0) 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), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; 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 | Uncertain | 1 | -5.120 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.97 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.26 | Pathogenic | 0.13 | Tolerated | 3.77 | 5 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.3009C>G | S1003R 2D  AIThe SynGAP1 missense variant S1003R (ClinVar ID 1798770.0) is listed as Uncertain in ClinVar and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic), and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect, which contrasts with the ClinVar designation of Uncertain. Thus, the variant is most likely pathogenic, contradicting the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||
| c.3020G>A | S1007N 2D AIThe SynGAP1 missense variant S1007N is listed in ClinVar (ID 2759915.0) as Benign and is not reported 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. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of high‑accuracy predictors (including the SGM‑Consensus) indicate a benign impact, and the single uncertain AlphaMissense‑Optimized result does not overturn this consensus. Therefore, 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 | Benign | 1 | -5.113 | Likely Benign | 0.803 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -1.54 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.2294G>A | S765N 2D AIThe SynGAP1 missense variant S765N (ClinVar ID 2979632.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.098 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 0.094 | Likely Benign | -0.94 | Neutral | 0.985 | Probably Damaging | 0.950 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 3.64 | 6 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.3977C>G | P1326R 2D  AIThe SynGAP1 missense variant P1326R is listed in ClinVar (ID 2429486.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.097 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.82 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| c.169C>T | L57F 2D  AIThe SynGAP1 missense variant L57F (ClinVar ID 1973575.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion aligns with the ClinVar “Uncertain” status, as it does not contradict the current classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | -5.096 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.051 | Likely Benign | -0.78 | Neutral | 0.824 | Possibly Damaging | 0.879 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||
| c.3209G>A | R1070K 2D AIThe SynGAP1 missense variant R1070K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta results are unavailable. Based on the unanimous benign predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | -5.093 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.049 | Benign | 0.048 | Benign | 3.86 | Benign | 0.09 | Tolerated | 3.77 | 5 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||
| c.3209_3210delinsCA | R1070T 2D  AIThe SynGAP1 missense variant R1070T is listed in ClinVar (ID 2759838.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (which aggregates these three benign calls with the pathogenic AlphaMissense‑Default to yield a Likely Benign verdict). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and no Foldetta stability data is available. Overall, the balance of evidence leans toward a benign impact, 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 | Uncertain | 1 | -5.093 | Likely Benign | 0.860 | Likely Pathogenic | Ambiguous | -2.35 | Neutral | 0.948 | Possibly Damaging | 0.507 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||
| c.2282G>C | R761P 2D  AIThe SynGAP1 missense variant R761P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441747‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions point to a benign impact, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 3 | 6-33441747-G-C | 1 | 6.20e-7 | -5.091 | Likely Benign | 0.640 | Likely Pathogenic | Likely Benign | 0.201 | Likely Benign | -1.89 | Neutral | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.69 | Benign | 0.38 | Tolerated | 3.99 | 5 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||
| c.3194C>T | P1065L 2D AIThe SynGAP1 missense variant P1065L is listed in ClinVar as Benign and is present in gnomAD (ID 6‑33443746‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the balance of evidence (5 benign vs. 4 pathogenic predictions) and the high‑accuracy benign call support a benign classification, aligning with the ClinVar status and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 1 | 6-33443746-C-T | 14 | 8.71e-6 | -5.085 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -2.94 | Deleterious | 0.950 | Possibly Damaging | 0.419 | Benign | 2.01 | Pathogenic | 0.00 | Affected | 4.32 | 2 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||
| c.2405G>A | G802D 2D  AIThe SynGAP1 missense variant G802D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33442957‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all classifying the change as benign. No tool predicts a pathogenic outcome. The high‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | Uncertain | 1 | 6-33442957-G-A | 1 | 6.20e-7 | -5.083 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -0.38 | Neutral | 0.126 | Benign | 0.138 | Benign | 2.72 | Benign | 0.09 | Tolerated | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||
| c.2548G>A | G850R 2D AIThe SynGAP1 missense variant G850R is listed in ClinVar with an uncertain significance (ClinVar ID 2042462.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign and the SGM‑Consensus indicating a likely benign outcome; Foldetta, a protein‑folding stability method, did not provide a result for this substitution. Overall, the preponderance of evidence points to a benign impact, which aligns 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 Benign | Uncertain | 1 | -5.082 | Likely Benign | 0.398 | Ambiguous | Likely Benign | 0.194 | Likely Benign | -0.07 | Neutral | 0.010 | Benign | 0.010 | Benign | 4.30 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.2560C>T | R854C 2D AIThe SynGAP1 missense variant R854C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443112‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; Foldetta results are not available. Overall, the majority of computational evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443112-C-T | 3 | 1.86e-6 | -5.082 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.174 | Likely Benign | -2.48 | Neutral | 1.000 | Probably Damaging | 0.947 | Probably Damaging | 4.05 | Benign | 0.01 | Affected | 3.88 | 3 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||
| c.2324G>C | R775P 2D AIThe SynGAP1 missense variant R775P (ClinVar ID 2959355.0) is classified as Benign in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, consistent with the ClinVar designation, and there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -5.072 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -0.79 | Neutral | 0.971 | Probably Damaging | 0.944 | Probably Damaging | 4.13 | Benign | 0.07 | Tolerated | 3.64 | 6 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||
| c.2825C>T | P942L 2D AIThe SynGAP1 missense variant P942L is listed in ClinVar (ID 2851884.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443377‑C‑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” 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 ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443377-C-T | 4 | 2.48e-6 | -5.063 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -2.00 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.37 | Pathogenic | 0.00 | Affected | 4.32 | 4 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33438843-T-C | 3 | 1.86e-6 | -5.056 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.203 | Likely Benign | -0.40 | Likely Benign | 0.2 | 0.35 | Likely Benign | -0.03 | Likely Benign | 0.47 | Likely Benign | -3.81 | Deleterious | 0.993 | Probably Damaging | 0.993 | Probably Damaging | 3.32 | Benign | 0.05 | Affected | 3.37 | 35 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||
| 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 | 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 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||
| c.2702C>T | A901V 2D  AIThe SynGAP1 missense variant A901V is listed in ClinVar (ID 934469.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33443254‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports 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 | Uncertain | 2 | 6-33443254-C-T | 2 | 1.24e-6 | -5.043 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.83 | Neutral | 0.106 | Benign | 0.009 | Benign | 2.64 | Benign | 0.17 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| 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 | 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 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.971G>A | R324Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324Q is listed in ClinVar with an uncertain significance (ClinVar ID 2572558.0) and is present in gnomAD (ID 6‑33437876‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Protein‑stability predictions from FoldX, Rosetta, and the combined Foldetta method are all uncertain. Overall, the consensus of available computational evidence points to a benign effect for R324Q, which is consistent with its ClinVar status of uncertain significance rather than a pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 3 | 6-33437876-G-A | 3 | 1.86e-6 | -5.001 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.307 | Likely Benign | 0.56 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.60 | Ambiguous | 1.02 | Destabilizing | -1.17 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.92 | Pathogenic | 0.41 | Tolerated | 3.39 | 22 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| c.3922C>T | R1308C 2D AIThe SynGAP1 missense variant R1308C is listed in ClinVar with an “Uncertain” significance and is present in the gnomAD database (ID 6‑33451796‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect 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 verdict. 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, and this assessment does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 2 | 6-33451796-C-T | 4 | 2.48e-6 | -4.994 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.352 | Likely Benign | -4.89 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.31 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.140G>A | R47Q 2D AIThe SynGAP1 missense variant R47Q is listed in ClinVar (ID 436920.0) as Benign and is present in gnomAD (6‑33423549‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Benign, and no Foldetta data to influence the conclusion. Overall, the majority of evidence points to a benign impact, consistent with the ClinVar classification; there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33423549-G-A | 4 | 2.48e-6 | -4.989 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.57 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| c.2474C>T | S825L 2D AIThe SynGAP1 missense variant S825L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443026‑C‑T). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” and the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Uncertain | 1 | 6-33443026-C-T | 1 | 6.20e-7 | -4.987 | Likely Benign | 0.910 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -4.30 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -2 | -3 | 4.6 | 26.08 | |||||||||||||||||||||||||||
| c.187G>A | E63K 2D  AIThe SynGAP1 E63K missense variant (ClinVar ID 2830630.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict a pathogenic outcome. AlphaMissense‑Optimized is inconclusive, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. Overall, the high‑accuracy consensus leans toward a benign effect, and this assessment does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.976 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.70 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||
| c.2582C>T | S861L 2D AIThe SynGAP1 missense variant S861L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443134‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome. 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 benign. No Foldetta stability prediction is available for this variant. Overall, the computational evidence overwhelmingly 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 | Uncertain | 1 | 6-33443134-C-T | 2 | 1.24e-6 | -4.966 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -2.10 | Neutral | 0.904 | Possibly Damaging | 0.355 | Benign | 3.93 | Benign | 0.07 | Tolerated | 4.32 | 3 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||
| c.2704G>A | A902T 2D AIThe SynGAP1 missense variant A902T is listed in ClinVar (ID 1027238.0) as benign and is observed in gnomAD (variant ID 6‑33443256‑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 high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of computational evidence supports a benign impact, consistent with the ClinVar annotation, and there is no contradiction between the predictions and the clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33443256-G-A | 36 | 2.23e-5 | -4.966 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.11 | Neutral | 0.951 | Possibly Damaging | 0.617 | Possibly Damaging | 2.61 | Benign | 0.01 | Affected | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.2852A>G | H951R 2D  AIThe SynGAP1 missense variant H951R is listed in ClinVar as Pathogenic (ClinVar ID 1003739.0) and is not reported in gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Based on the collective predictions, the variant is most likely benign, which contradicts its ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Pathogenic | 1 | -4.964 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.185 | Likely Benign | -1.08 | Neutral | 0.048 | Benign | 0.029 | Benign | 5.46 | Benign | 0.24 | Tolerated | 3.77 | 5 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||
| c.2111G>C | S704T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while FoldX remains inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the aggregate evidence indicates that S704T is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -4.930 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.29 | Likely Benign | -1.72 | Neutral | 0.525 | Possibly Damaging | 0.107 | Benign | 3.45 | Benign | 0.07 | Tolerated | 3.47 | 10 | 1 | 1 | 0.1 | 14.03 | 201.7 | -18.0 | 0.0 | 0.0 | -0.2 | 0.7 | X | Potentially Benign | Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. Similarly, in the variant simulations, the hydroxyl side chain of Thr704 forms hydrogen bonds with the amide groups of Ala707 and Leu708. Thus, the residue swap does not cause any apparent structural change. | |||||||||||
| c.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 | 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 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.3958C>T | P1320S 2D AIThe SynGAP1 missense variant P1320S is listed in ClinVar (ID 469160.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451832‑C‑T). 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, 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 as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33451832-C-T | 2 | 1.28e-6 | -4.928 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.69 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
| c.3961C>T | P1321S 2D AIThe SynGAP1 missense variant P1321S is listed in ClinVar (ID 1806027.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33451835‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| c.3181G>A | G1061S 2D AIThe SynGAP1 missense variant G1061S is listed in ClinVar (ID 3571724.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods supports a benign classification for G1061S, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.891 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.283 | Likely Benign | -0.68 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.00 | Benign | 0.00 | Affected | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3364G>A | G1122S 2D AIThe SynGAP1 missense variant G1122S is listed in ClinVar as a benign alteration (ClinVar ID 643187.0) and is present in gnomAD (gnomAD ID 6‑33443916‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely benign, while Foldetta’s protein‑folding stability result is unavailable. Overall, the variant is most likely benign, and this assessment is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign/Likely benign | 2 | 6-33443916-G-A | 27 | 1.79e-5 | -4.880 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.189 | Likely Benign | -0.08 | Neutral | 0.022 | Benign | 0.006 | Benign | 4.89 | Benign | 0.92 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.3835G>A | A1279T 2D AIThe SynGAP1 missense variant A1279T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33447883‑G‑A). All available in silico predictors report a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized are benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign; Foldetta results are not available. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33447883-G-A | 2 | 1.29e-6 | -4.871 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.30 | Neutral | 0.001 | Benign | 0.000 | Benign | 2.71 | Benign | 0.09 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.3557C>T | S1186L 2D AIThe SynGAP1 missense variant S1186L (ClinVar ID 930096.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33444592‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized reports an uncertain outcome. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a tie, leaving the result inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available output for this variant. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not contradict the ClinVar Uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | Uncertain | 1 | 6-33444592-C-T | -4.829 | Likely Benign | 0.923 | Likely Pathogenic | Ambiguous | 0.177 | Likely Benign | -2.58 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.65 | Benign | 0.04 | Affected | 3.82 | 4 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.3929C>T | T1310M 2D  AIThe SynGAP1 missense variant T1310M is listed in ClinVar (ID 2160201.0) as Benign and is present in gnomAD (gnomAD ID 6‑33451803‑C‑T). All evaluated in‑silico predictors report a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33451803-C-T | 17 | 1.05e-5 | -4.822 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||
| c.1055C>A | T352N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352N is listed in ClinVar as Benign (ClinVar ID 590151.0) and is present in the gnomAD database (gnomAD ID 6‑33437960‑C‑A). Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly report a benign effect, whereas only FATHMM predicts pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also benign. No predictions or stability analyses are missing or inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Likely Benign | 1 | 6-33437960-C-A | 2 | 1.24e-6 | -4.817 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.20 | Likely Benign | 0.0 | -0.04 | Likely Benign | 0.08 | Likely Benign | 0.45 | Likely Benign | -0.92 | Neutral | 0.255 | Benign | 0.057 | Benign | 1.75 | Pathogenic | 0.19 | Tolerated | 3.37 | 25 | 0 | 0 | -2.8 | 13.00 | 208.4 | -14.5 | -0.2 | 0.1 | -0.1 | 0.0 | X | Potentially Benign | Thr352 is located in a short α helical section within a loop connecting two β strands (res. Gly341-Pro349, res. Thr359-Pro364) originating from two different anti-parallel β sheets of the C2 domain. In the WT simulations, the side chain hydroxyl and backbone amide groups of Thr354 form hydrogen bonds with the backbone carbonyl group of Pro349 at the end of the preceding β strand. This arrangement likely stabilizes the α helical section and aids in folding, keeping the short secondary structure element intact in the variant simulations. However, the carboxamide group of the Asn352 side chain does not form hydrogen bonds with the backbone carbonyl group of Pro349. Instead, it packs against the cyclic ring and forms hydrogen bonds with the phenol group of the Tyr363 side chain in the other β strand. | ||||||||
| c.2359C>A | P787T 2D  AISynGAP1 missense variant P787T is listed in ClinVar as benign (ClinVar ID 862728.0) and is present in gnomAD (6‑33442911‑C‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by AlphaMissense‑Default, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized result is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, which contradicts the ClinVar benign classification. Thus, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | Likely Benign | 1 | 6-33442911-C-A | 17 | 1.05e-5 | -4.813 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.258 | Likely Benign | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.46 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||
| c.2354G>A | R785H 2D AIThe SynGAP1 R785H missense variant (ClinVar ID 2321588.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33442906‑G‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, does not provide a result for this variant. Overall, the majority of computational predictions (five pathogenic versus three benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current predictions, 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. | SH3-binding motif | Uncertain | 2 | 6-33442906-G-A | 4 | 2.50e-6 | -4.782 | Likely Benign | 0.388 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.947 | Probably Damaging | 2.25 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.2960A>G | D987G 2D  AIThe SynGAP1 missense variant D987G (ClinVar ID 1061058.0) is listed as ClinVar status Uncertain and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and ESM1b, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further indicate that AlphaMissense‑Optimized is uncertain, while Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, aligning with the SGM‑Consensus but contradicting the ClinVar Uncertain designation. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment is in conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Uncertain | 1 | -4.782 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.79 | Deleterious | 0.943 | Possibly Damaging | 0.808 | Possibly Damaging | 2.45 | Pathogenic | 0.07 | Tolerated | 4.32 | 2 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.3404A>C | K1135T 2D  AIThe SynGAP1 missense variant K1135T is listed in ClinVar (ID 1166087.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443956‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443956-A-C | 1 | 6.75e-7 | -4.778 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | -0.90 | Neutral | 0.411 | Benign | 0.321 | Benign | 5.46 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||
| c.379C>T | R127W 2D AISynGAP1 missense variant R127W is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools show a 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. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Consequently, the evidence does not favor a clear benign or pathogenic outcome; the predictions are balanced and align with the ClinVar designation of Uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -4.776 | Likely Benign | 0.806 | Likely Pathogenic | Ambiguous | 0.118 | Likely Benign | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.420 | Benign | 3.88 | Benign | 0.00 | Affected | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3178G>A | G1060S 2D AIThe SynGAP1 missense variant G1060S is listed in ClinVar with an uncertain significance (ClinVar ID 1512003.0) and is present in gnomAD (variant ID 6‑33443730‑G‑A). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this benign view: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443730-G-A | -4.759 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.376 | Likely Benign | -0.08 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.69 | Benign | 0.49 | Tolerated | 4.32 | 2 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.3902C>G | P1301R 2D AIThe SynGAP1 missense variant P1301R is listed in ClinVar with an uncertain significance (ClinVar ID 2092739.0) and is present in gnomAD (ID 6‑33451776‑C‑G). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. In summary, all available predictions agree on a benign impact, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33451776-C-G | 15 | 9.30e-6 | -4.753 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.13 | Neutral | 0.077 | Benign | 0.059 | Benign | 2.81 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||
| c.2506A>G | S836G 2D AIThe SynGAP1 missense variant S836G is listed in ClinVar (ID 537003.0) with an uncertain significance annotation and is observed in the gnomAD database (variant ID 6‑33443058‑A‑G). Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. Foldetta, a protein‑folding stability predictor, did not return a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not conflict with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443058-A-G | 4 | 2.48e-6 | -4.749 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.65 | Neutral | 0.006 | Benign | 0.019 | Benign | 2.54 | Benign | 0.39 | Tolerated | 3.77 | 5 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||
| c.2557G>C | G853R 2D AIThe SynGAP1 missense variant G853R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore point to a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and no Foldetta data is available. Overall, the majority of evidence supports a benign classification, which does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.749 | Likely Benign | 0.366 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -1.27 | Neutral | 0.846 | Possibly Damaging | 0.624 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2591C>T | A864V 2D AIThe SynGAP1 missense variant A864V is listed in ClinVar with an uncertain significance (ClinVar ID 655662.0) and is observed in gnomAD (ID 6‑33443143‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta results are unavailable. Based on the preponderance of evidence, 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. | Likely Benign | Uncertain | 2 | 6-33443143-C-T | 6 | 3.72e-6 | -4.749 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -1.35 | Neutral | 0.767 | Possibly Damaging | 0.119 | Benign | 2.45 | Pathogenic | 0.30 | Tolerated | 3.82 | 4 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| c.3196C>T | P1066S 2D AIThe SynGAP1 missense variant P1066S is listed in ClinVar as Pathogenic (ClinVar ID 1343237.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, which contradicts the ClinVar pathogenic classification. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Pathogenic | 1 | -4.746 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.47 | Neutral | 0.972 | Probably Damaging | 0.850 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 4.32 | 2 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.121C>T | R41C 2D AIThe SynGAP1 missense variant R41C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423530‑C‑T). 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). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and no result is available from Foldetta (protein‑folding stability). Taken together, the majority of evidence points to a benign impact for R41C, 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 | Conflicting | 3 | 6-33423530-C-T | 7 | 4.34e-6 | -4.745 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.10 | Neutral | 0.976 | Probably Damaging | 0.919 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||
| c.3979C>T | P1327S 2D AIThe SynGAP1 missense variant P1327S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.256G>A | V86I 2D AIThe SynGAP1 missense variant V86I is listed in ClinVar (ID 588267.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign or likely benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the majority of predictions indicate that V86I is most likely benign, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.726 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.31 | Neutral | 0.267 | Benign | 0.097 | Benign | 3.94 | Benign | 0.00 | Affected | 4.32 | 1 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||
| c.4006G>A | E1336K 2D AISynGAP1 missense variant E1336K is listed in ClinVar as benign (ClinVar ID 984837.0) and is present in gnomAD (6‑33451880‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, aligning with the ClinVar designation, though a single high‑accuracy tool suggests pathogenicity. Thus, the variant is most likely benign, and this conclusion does not contradict its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 2 | 6-33451880-G-A | 6 | 4.20e-6 | -4.697 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.272 | Likely Benign | -2.44 | Neutral | 0.748 | Possibly Damaging | 0.079 | Benign | 3.23 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||
| c.3328A>G | S1110G 2D AIThe SynGAP1 missense variant S1110G is listed in ClinVar (ID 1722210.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; 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 aligns with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | -4.674 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -2.26 | Neutral | 0.036 | Benign | 0.026 | Benign | 2.19 | Pathogenic | 0.08 | Tolerated | 4.32 | 2 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.2924C>A | T975N 2D AIThe SynGAP1 missense variant T975N is listed in ClinVar (ID 942242.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443476‑C‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes. Only polyPhen‑2 HumDiv 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443476-C-A | 1 | 6.20e-7 | -4.671 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.58 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 4.13 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||
| c.866T>C | M289T 2D  AIThe SynGAP1 missense variant M289T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a benign effect. Taken together, the majority of evidence indicates that M289T is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | -4.668 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.222 | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.17 | Likely Benign | 0.45 | Likely Benign | -0.01 | Likely Benign | -0.47 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 1.83 | Pathogenic | 0.57 | Tolerated | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||
| c.2414T>C | L805P 2D AIThe SynGAP1 missense variant L805P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no Foldetta data are available. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | Uncertain | 1 | -4.661 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.272 | Likely Benign | -3.40 | Deleterious | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.2724G>C | Q908H 2D  AIThe SynGAP1 missense variant Q908H is listed in ClinVar (ID 436926.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443276‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 4 | 6-33443276-G-C | 1 | 6.20e-7 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||
| c.2596G>A | V866I 2D AIThe SynGAP1 missense variant V866I is listed in ClinVar with an “Uncertain” status (ClinVar ID 536995.0) and is present in gnomAD (6‑33443148‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33443148-G-A | 5 | 3.10e-6 | -4.652 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.39 | Neutral | 0.957 | Probably Damaging | 0.541 | Possibly Damaging | 2.69 | Benign | 0.27 | Tolerated | 3.82 | 4 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.3041G>T | G1014V 2D  AIThe SynGAP1 missense variant G1014V is listed in ClinVar (ID 809922.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.612 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.47 | Neutral | 0.818 | Possibly Damaging | 0.377 | Benign | 2.72 | Benign | 0.06 | Tolerated | 3.77 | 5 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
| c.3056G>A | R1019H 2D AIThe SynGAP1 missense variant R1019H is listed in ClinVar (ID 1195115.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443608‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for R1019H, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443608-G-A | 67 | 4.15e-5 | -4.610 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.95 | Neutral | 0.995 | Probably Damaging | 0.845 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.4000A>G | N1334D 2D  AIThe SynGAP1 missense variant N1334D (ClinVar ID 3653769.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33451874‑A‑G). 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), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, an inconclusive SGM Consensus (a 2‑vs‑2 majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no available Foldetta stability data. Overall, the majority of predictions (5/10) indicate pathogenicity, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, which does not contradict its ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33451874-A-G | -4.584 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -3.06 | Deleterious | 0.886 | Possibly Damaging | 0.522 | Possibly Damaging | 3.55 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.416G>A | S139N 2D AIThe SynGAP1 missense variant S139N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432713‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33432713-G-A | 3 | 2.22e-6 | -4.584 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.75 | Neutral | 0.149 | Benign | 0.047 | Benign | 4.14 | Benign | 0.24 | Tolerated | 3.61 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.3237C>A | S1079R 2D AIThe SynGAP1 missense variant S1079R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443789‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443789-C-A | 4 | 2.51e-6 | -4.579 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.3237C>G | S1079R 2D AIThe SynGAP1 missense variant S1079R is listed in ClinVar (ID 1047537.0) as Benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. High‑accuracy assessments therefore show a benign consensus (SGM‑Consensus) with one uncertain AlphaMissense‑Optimized prediction and no destabilizing Foldetta evidence. Overall, the majority of predictions support 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 | Benign | 1 | -4.579 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.3192G>C | Q1064H 2D AIThe SynGAP1 missense variant Q1064H is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.576 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.66 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 4.15 | Benign | 0.05 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||
| c.1663G>A | V555I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -4.544 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.253 | Likely Benign | -0.82 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.62 | Ambiguous | -0.55 | Ambiguous | 0.45 | Neutral | 0.002 | Benign | 0.002 | Benign | -1.26 | Pathogenic | 1.00 | Tolerated | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||
| c.2578G>A | V860I 2D AIThe SynGAP1 missense variant V860I is catalogued in ClinVar as a benign alteration (ClinVar ID 411591.0) and is present in the gnomAD database (gnomAD ID 6‑33443130‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability prediction is available for this variant. Overall, the consensus of computational evidence strongly favors a benign impact, aligning with the ClinVar designation and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33443130-G-A | 21 | 1.30e-5 | -4.516 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.42 | Neutral | 0.009 | Benign | 0.006 | Benign | 4.24 | Benign | 0.00 | Affected | 3.77 | 5 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.3287A>C | E1096A 2D AIThe SynGAP1 missense variant E1096A is listed in ClinVar (ID 2579889.0) with an uncertain significance annotation and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv assigns a pathogenic label, while AlphaMissense‑Default remains uncertain. 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, has no available result for this variant. Overall, the aggregate 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 | Uncertain | 1 | -4.504 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -1.37 | Neutral | 0.626 | Possibly Damaging | 0.184 | Benign | 2.77 | Benign | 0.16 | Tolerated | 3.77 | 5 | -1 | 0 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.4003G>A | G1335S 2D AIThe SynGAP1 missense variant G1335S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451877‑G‑A). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that G1335S is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Conflicting | 2 | 6-33451877-G-A | 3 | 2.37e-6 | -4.495 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.2657C>T | A886V 2D AIThe SynGAP1 missense variant A886V is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443209‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Tools that predict a pathogenic effect are 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) also as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443209-C-T | 18 | 1.12e-5 | -4.478 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.20 | Neutral | 0.888 | Possibly Damaging | 0.314 | Benign | 2.17 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| c.2324G>A | R775Q 2D AIThe SynGAP1 missense variant R775Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442482‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the same set of high‑confidence predictors) is “Likely Benign.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33442482-G-A | 11 | 1.41e-5 | -4.476 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.63 | Neutral | 0.969 | Probably Damaging | 0.863 | Possibly Damaging | 4.17 | Benign | 0.16 | Tolerated | 3.64 | 6 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| c.2750C>G | P917R 2D AIThe SynGAP1 missense variant P917R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443302‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443302-C-G | 5 | 3.10e-6 | -4.475 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.70 | Neutral | 0.642 | Possibly Damaging | 0.316 | Benign | 2.68 | Benign | 0.00 | Affected | 3.77 | 5 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||
| c.2983C>T | P995S 2D AIThe SynGAP1 missense variant P995S is listed in ClinVar (ID 436929.0) 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), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The only tool that predicts a pathogenic outcome is SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta) stability result is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, point to a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.457 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.03 | Neutral | 0.011 | Benign | 0.015 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.2987C>G | P996R 2D AIThe SynGAP1 missense variant P996R is listed in ClinVar (ID 2808854.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates a benign impact. This prediction aligns with the ClinVar benign classification and does not contradict the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -4.457 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -1.04 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.26 | Benign | 0.01 | Affected | 4.32 | 4 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| c.3103C>A | P1035T 2D AIThe SynGAP1 missense variant P1035T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence from AlphaMissense‑Optimized and the SGM‑Consensus both support a benign classification, while the absence of a Foldetta result does not alter this view. Overall, the majority of predictions indicate a benign effect, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.447 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.96 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 2.72 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.29G>A | R10Q 2D AIThe SynGAP1 missense variant R10Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33420293‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that R10Q is most likely benign, which does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33420293-G-A | 20 | 1.30e-5 | -4.438 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.03 | Neutral | 0.121 | Benign | 0.004 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.92G>A | R31Q 2D AIThe SynGAP1 missense variant R31Q is listed in ClinVar (ID 1977609.0) with an “Uncertain” status and is present in gnomAD (6‑33423501‑G‑A). 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, which does not contradict the ClinVar “Uncertain” classification and suggests the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33423501-G-A | 7 | 4.34e-6 | -4.434 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.92 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.3290C>T | P1097L 2D AIThe SynGAP1 missense variant P1097L is listed in ClinVar as Benign (ClinVar ID 2060978.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). 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 benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign impact, and this conclusion is consistent with the ClinVar designation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -4.410 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -2.07 | Neutral | 0.611 | Possibly Damaging | 0.198 | Benign | 2.64 | Benign | 0.05 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.2101C>T | P701S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P701S (ClinVar ID 2995856.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33441360‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). No tool in the dataset predicts a pathogenic outcome; all remaining predictions are either benign or uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33441360-C-T | 3 | 1.86e-6 | -4.375 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.132 | Likely Benign | 1.33 | Ambiguous | 0.0 | 0.12 | Likely Benign | 0.73 | Ambiguous | -0.36 | Likely Benign | 0.78 | Neutral | 0.044 | Benign | 0.025 | Benign | 3.48 | Benign | 1.00 | Tolerated | 3.47 | 10 | -1 | 1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||
| c.2962C>T | L988F 2D AIThe SynGAP1 missense variant L988F is listed in ClinVar (ID 968833.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443514‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443514-C-T | 1 | 6.20e-7 | -4.368 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -1.70 | Neutral | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.69 | Benign | 0.00 | Affected | 4.32 | 2 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||
| c.1511A>G | K504R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438543‑A‑G). Consensus from most in‑silico predictors is benign: REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect, while only FATHMM predicts pathogenicity. Uncertain calls come from Rosetta and premPS. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33438543-A-G | 2 | 1.24e-6 | -4.365 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.238 | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.32 | Likely Benign | 0.94 | Ambiguous | -2.16 | Neutral | 0.002 | Benign | 0.015 | Benign | -1.41 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||
| 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 | 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 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||
| c.304T>G | L102V 2D  AIThe SynGAP1 missense variant L102V is listed in ClinVar (ID 1925749.0) with an “Uncertain” status and is present in gnomAD (6‑33432169‑T‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33432169-T-G | 1 | 6.20e-7 | -4.316 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.102 | Likely Benign | 0.32 | Neutral | 0.880 | Possibly Damaging | 0.899 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||
| c.3705G>A | M1235I 2D AIThe SynGAP1 missense variant M1235I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Uncertain | 1 | -4.312 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.44 | Neutral | 0.139 | Benign | 0.056 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| 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 | 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 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.913A>G | T305A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T305A variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437818‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. 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 | C2 | Conflicting | 2 | 6-33437818-A-G | 13 | 8.05e-6 | -4.307 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.30 | Ambiguous | 0.6 | 1.55 | Ambiguous | 1.43 | Ambiguous | 0.77 | Ambiguous | -2.10 | Neutral | 0.939 | Possibly Damaging | 0.645 | Possibly Damaging | 1.76 | Pathogenic | 0.12 | Tolerated | 3.40 | 20 | 1 | 0 | 2.5 | -30.03 | 177.9 | 43.5 | -0.2 | 0.1 | 0.4 | 0.0 | Uncertain | The hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||
| c.3142G>C | G1048R 2D AIThe SynGAP1 missense variant G1048R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.2200C>T | P734S 2D AIThe SynGAP1 missense variant P734S is listed in ClinVar with an uncertain significance (ClinVar ID 2283225.0) and is present in the gnomAD database (gnomAD ID 6‑33441665‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this benign assessment: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33441665-C-T | 2 | 1.24e-6 | -4.291 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -2.44 | Neutral | 0.344 | Benign | 0.048 | Benign | 2.77 | Benign | 0.11 | Tolerated | 3.64 | 6 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| 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 | 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 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.3508A>G | S1170G 2D AIThe SynGAP1 missense variant S1170G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Uncertain | 1 | -4.288 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -0.81 | Neutral | 0.241 | Benign | 0.229 | Benign | 5.31 | Benign | 0.54 | Tolerated | 4.32 | 4 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.2735C>A | T912N 2D AIThe SynGAP1 missense variant T912N is listed in ClinVar with an uncertain significance (ClinVar ID 2337624.0) 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, 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 (FoldX‑MD/Rosetta) stability result is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.260 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.15 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||
| c.2741A>T | D914V 2D  AIThe SynGAP1 missense variant D914V is listed in ClinVar (ID 2582846.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools 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, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; Foldetta results are unavailable. Overall, the balance of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.260 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.187 | Likely Benign | -2.24 | Neutral | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -2 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||
| 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 | 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 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| c.3121C>T | P1041S 2D AIThe SynGAP1 missense variant P1041S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443673‑C‑T). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443673-C-T | 1 | 6.20e-7 | -4.246 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.344 | Likely Benign | -2.72 | Deleterious | 0.664 | Possibly Damaging | 0.283 | Benign | 5.48 | Benign | 0.11 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
| c.2214T>G | S738R 2D AIThe SynGAP1 missense variant S738R is listed in ClinVar (ID 1592652.0) as Benign and is present in gnomAD (variant ID 6‑33441679‑T‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33441679-T-G | 1 | 6.20e-7 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.865A>G | M289V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M289V is reported in ClinVar as Benign (ClinVar ID 2122760.0) and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all predict benign, while only FATHMM predicts pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates benign. No prediction or stability result is inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Benign | 1 | -4.239 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.150 | Likely Benign | 1.09 | Ambiguous | 0.1 | -0.27 | Likely Benign | 0.41 | Likely Benign | 0.24 | Likely Benign | -0.36 | Neutral | 0.136 | Benign | 0.054 | Benign | 1.80 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | 2 | 1 | 2.3 | -32.06 | 204.2 | 51.0 | 0.0 | 0.0 | 0.2 | 0.0 | X | Potentially Benign | The hydrophobic residue Met289, located in a β hairpin linking two anti-parallel β sheet strands (res. Met289-Arg299, res. Arg272-Leu286), is swapped for another hydrophobic residue, valine. In the variant simulations, the branched hydrocarbon side chain of Val289 packs against the phenol group of the Tyr291 side chain but is unable to form methionine-aromatic interactions. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. However, based on the simulations, the residue swap does not cause adverse effects on the structure. | |||||||||||
| c.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 | 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 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||
| c.382C>A | P128T 2D AIThe SynGAP1 missense variant P128T is listed in ClinVar with an “Uncertain” status (ClinVar ID 2801315.0) and is present in gnomAD (ID 6‑33432247‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33432247-C-A | 1 | 6.20e-7 | -4.217 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.19 | Benign | 0.35 | Tolerated | 3.74 | 4 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||
| 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 | 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 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
| c.2282G>A | R761Q 2D AIThe SynGAP1 missense variant R761Q is listed in ClinVar (ID 2882770.0) with an “Uncertain” status and is present in gnomAD (6‑33441747‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33441747-G-A | 11 | 6.81e-6 | -4.187 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -0.63 | Neutral | 0.996 | Probably Damaging | 0.878 | Possibly Damaging | 2.75 | Benign | 0.40 | Tolerated | 3.99 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.2714G>A | R905H 2D AIThe SynGAP1 missense variant R905H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443266‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta’s protein‑folding stability analysis is unavailable for this variant. Overall, the majority 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 | Uncertain | 1 | 6-33443266-G-A | 8 | 4.96e-6 | -4.182 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.192 | Likely Benign | -1.11 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.59 | Benign | 0.09 | Tolerated | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.3100C>G | P1034A 2D  AIThe SynGAP1 missense variant P1034A is listed in ClinVar as Benign (ClinVar ID 1901716.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome, representing the sole discordant signal. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates a benign impact. This prediction aligns with the ClinVar status, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -4.174 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -2.44 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.2503C>A | L835M 2D  AIThe SynGAP1 missense variant L835M is listed in ClinVar (ID 2731331.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus also indicating a likely benign outcome, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence—including the high‑accuracy tools—supports a benign classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -4.153 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.45 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.67 | Benign | 0.12 | Tolerated | 3.77 | 5 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| 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 | 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 | 1 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.3574C>G | L1192V 2D AIThe SynGAP1 missense variant L1192V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. 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 | Coiled-coil | Uncertain | 1 | -4.132 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.041 | Likely Benign | -0.89 | Neutral | 0.779 | Possibly Damaging | 0.527 | Possibly Damaging | 2.69 | Benign | 0.16 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||
| c.74G>A | R25Q 2D AIThe SynGAP1 missense variant R25Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423483‑G‑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, and 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, 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 | Uncertain | 1 | 6-33423483-G-A | 15 | 9.29e-6 | -4.126 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.70 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.3251C>A | P1084H 2D AIThe SynGAP1 missense variant P1084H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443803‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which reports “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Thus, the variant is most likely benign, and its prediction profile does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443803-C-A | 1 | 6.31e-7 | -4.125 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -3.16 | Deleterious | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | -2 | 0 | -1.6 | 40.02 | |||||||||||||||||||||||||||
| c.2608C>G | L870V 2D AIThe SynGAP1 missense variant L870V is listed in ClinVar (ID 946946.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.123 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.64 | Benign | 0.12 | Tolerated | 3.88 | 3 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.3995C>T | T1332M 2D AISynGAP1 missense variant T1332M is listed as Benign in ClinVar (ID 794425) and is present in gnomAD (6‑33451869‑C‑T). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized returned an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and no Foldetta stability data are available. Overall, the majority of evidence points toward a pathogenic effect, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 1 | 6-33451869-C-T | 20 | 1.86e-5 | -4.107 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||
| c.5G>A | S2N 2D AIThe SynGAP1 missense variant S2N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33420269‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 preponderance of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33420269-G-A | 3 | 1.96e-6 | -4.104 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.36 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.2989G>A | A997T 2D AIThe SynGAP1 missense variant A997T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four high‑accuracy predictors) is benign; Foldetta results are unavailable. Taken together, the majority of computational evidence indicates 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 | Uncertain | 1 | -4.102 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.62 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 4 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.2998A>G | I1000V 2D  AIThe SynGAP1 missense variant I1000V is listed in ClinVar (ID 2572013.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that assess evolutionary conservation and structural impact (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default) all converge on a benign outcome. No tool in the dataset predicts pathogenicity. High‑accuracy predictors reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | -4.102 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.20 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.76 | Benign | 0.81 | Tolerated | 4.32 | 4 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.2225G>A | R742Q 2D AIThe SynGAP1 missense variant R742Q is listed in ClinVar (ID 928481.0) with an uncertain significance annotation and is observed in gnomAD (variant ID 6‑33441690‑G‑A). Consensus from multiple in‑silico predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—uniformly classify the change as benign. No tool in the dataset reports a pathogenic prediction. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. A protein‑folding stability analysis via Foldetta is not available for this variant. Overall, the computational evidence strongly favors a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. The variant is most likely benign, and this assessment does not contradict its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33441690-G-A | 24 | 1.49e-5 | -4.090 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.19 | Neutral | 0.032 | Benign | 0.007 | Benign | 2.73 | Benign | 0.07 | Tolerated | 4.32 | 2 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.3638A>G | N1213S 2D  AIThe SynGAP1 missense variant N1213S is listed in ClinVar as Benign (ClinVar ID 708250.0) and is present in the gnomAD database (gnomAD ID 6‑33446630‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Benign | 1 | 6-33446630-A-G | 13 | 8.05e-6 | -4.086 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.56 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.82 | Benign | 0.68 | Tolerated | 3.77 | 5 | 1 | 1 | 2.7 | -27.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||
| c.269T>A | V90E 2D  AIThe SynGAP1 missense variant V90E is listed in ClinVar (ID 971665.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools—SIFT and AlphaMissense‑Default—suggest a pathogenic outcome. When the high‑accuracy consensus is considered, AlphaMissense‑Optimized remains 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 assessment is available for this variant. Overall, the preponderance 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 | Uncertain | 1 | -4.079 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.00 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||
| c.2277G>A | M759I 2D AIThe SynGAP1 missense variant M759I is listed in ClinVar (ID 3686687.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441742‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33441742-G-A | 1 | 6.20e-7 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.3022G>A | D1008N 2D  AIThe SynGAP1 missense variant D1008N is listed in ClinVar (ID 1213097.0) as benign and is present in gnomAD (variant ID 6‑33443574‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote model of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence indicates a benign effect, consistent with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33443574-G-A | 3 | 1.86e-6 | -4.045 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.128 | Likely Benign | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.75 | Benign | 0.01 | Affected | 3.77 | 5 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||
| c.3920C>T | P1307L 2D AIThe SynGAP1 missense variant P1307L is listed in ClinVar (ID 1991214.0) as benign and is present in gnomAD (variant ID 6‑33451794‑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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “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 predictions, including the high‑accuracy consensus, indicate a benign impact. This conclusion aligns with the ClinVar benign classification and does not contradict the reported clinical status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33451794-C-T | 11 | 6.82e-6 | -4.044 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.292 | Likely Benign | -1.49 | Neutral | 0.779 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.04 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.3941C>T | P1314L 2D AIThe SynGAP1 missense variant P1314L is listed in ClinVar as a benign alteration (ClinVar ID 646689.0) and is present in the gnomAD database (gnomAD ID 6‑33451815‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification. Thus, the variant is most likely benign and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33451815-C-T | 2 | 1.24e-6 | -4.040 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.20 | Neutral | 0.421 | Benign | 0.066 | Benign | 4.19 | Benign | 0.05 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.187G>C | E63Q 2D  AIThe SynGAP1 missense variant E63Q is listed in ClinVar (ID 2132335.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.038 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -0.85 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.2690C>T | S897L 2D AIThe SynGAP1 missense variant S897L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same four high‑accuracy tools) also as benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.034 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -1.71 | Neutral | 0.901 | Possibly Damaging | 0.636 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.218G>A | R73K 2D AIThe SynGAP1 missense variant R73K is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33425826‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33425826-G-A | 2 | 1.24e-6 | -4.033 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.46 | Neutral | 0.053 | Benign | 0.007 | Benign | 4.14 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 3 | 0.6 | -28.01 | |||||||||||||||||||||||||||
| c.36C>G | S12R 2D AIThe SynGAP1 missense variant S12R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33420300‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign classification; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33420300-C-G | 4 | 2.59e-6 | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.223G>A | E75K 2D AIThe SynGAP1 missense variant E75K is listed in ClinVar as Benign (ClinVar ID 3360083.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign/Likely benign | 2 | -4.020 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.134 | Likely Benign | -1.12 | Neutral | 0.748 | Possibly Damaging | 0.017 | Benign | 4.07 | Benign | 0.00 | Affected | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||
| c.3858A>T | E1286D 2D  AIThe SynGAP1 missense variant E1286D is listed in ClinVar (ID 469159.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33447906‑A‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool in the set predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 4 | 6-33447906-A-T | 143 | 9.22e-5 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| c.2914C>T | P972S 2D AIThe SynGAP1 missense variant P972S (ClinVar ID 3361353.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443466‑C‑T). Consensus among most in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. Only SIFT classifies it as pathogenic, representing the sole discordant prediction. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability analysis is available for this residue. Overall, the preponderance of computational evidence points to a benign effect, which is consistent with the ClinVar designation of uncertainty rather than pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443466-C-T | 4 | 2.48e-6 | -4.008 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.28 | Benign | 0.05 | Affected | 4.32 | 2 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
| c.3859C>A | P1287T 2D AIThe SynGAP1 missense variant P1287T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33447907‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33447907-C-A | -3.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.22 | Neutral | 0.126 | Benign | 0.041 | Benign | 2.78 | Benign | 0.04 | Affected | 3.77 | 5 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.2971G>A | G991R 2D AIThe SynGAP1 missense variant G991R is listed in ClinVar (ID 1029090.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443523‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33443523-G-A | 8 | 4.96e-6 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.3238G>A | A1080T 2D AIThe SynGAP1 missense variant A1080T (ClinVar ID 1473274.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33443790‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, which does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443790-G-A | 17 | 1.06e-5 | -3.928 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.19 | Neutral | 0.253 | Benign | 0.042 | Benign | 4.10 | Benign | 0.60 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.3250C>G | P1084A 2D AIThe SynGAP1 missense variant P1084A is listed in ClinVar (ID 2827308.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Benign”). In contrast, PROVEAN and polyPhen‑2 HumDiv predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, 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 | Uncertain | 1 | -3.928 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.54 | Deleterious | 0.649 | Possibly Damaging | 0.157 | Benign | 4.05 | Benign | 0.35 | Tolerated | 3.77 | 5 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.3956C>G | A1319G 2D  AIThe SynGAP1 missense variant A1319G is listed in ClinVar (ID 1690510.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451830‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. 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 | Uncertain | 2 | 6-33451830-C-G | -3.927 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.74 | Neutral | 0.819 | Possibly Damaging | 0.581 | Possibly Damaging | 4.07 | Benign | 0.06 | Tolerated | 3.77 | 5 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.2369C>G | T790S 2D  AIThe SynGAP1 missense variant T790S is listed in ClinVar (ID 1020340.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | Uncertain | 1 | -3.914 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.39 | Pathogenic | 0.33 | Tolerated | 3.64 | 6 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2932C>T | P978S 2D AIThe SynGAP1 missense variant P978S is listed in ClinVar (ID 3379672.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign effect, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.913 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.07 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 4.22 | Benign | 0.48 | Tolerated | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2924C>T | T975I 2D  AIThe SynGAP1 missense variant T975I is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33443476‑C‑T). Prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443476-C-T | 6 | 3.72e-6 | -3.912 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.66 | Neutral | 0.411 | Benign | 0.239 | Benign | 4.11 | Benign | 0.66 | Tolerated | 4.32 | 2 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||
| c.50C>T | S17F 2D  AIThe SynGAP1 missense variant S17F is listed in ClinVar with an “Uncertain” status (ClinVar ID 3451958.0) and is present in gnomAD (ID 6‑33420314‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. 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 also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33420314-C-T | 10 | 6.49e-6 | -3.888 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.048 | Likely Benign | -0.99 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||
| c.1604G>C | S535T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535T is catalogued in ClinVar as benign (ClinVar ID 537005.0) and is observed in gnomAD (variant ID 6‑33438847‑G‑C). In silico prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. Only FATHMM predicts a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM Consensus is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the consensus of predictive tools and high‑accuracy methods indicates that the variant is most likely benign, consistent with its ClinVar classification and presence in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Benign | 1 | 6-33438847-G-C | 14 | 8.67e-6 | -3.886 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.177 | Likely Benign | 0.45 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.09 | Likely Benign | 0.17 | Likely Benign | -0.81 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.25 | Pathogenic | 0.25 | Tolerated | 3.37 | 35 | 1 | 1 | 0.1 | 14.03 | 201.3 | -17.3 | -0.1 | 0.7 | -0.2 | 0.1 | X | Potentially Benign | Ser535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | 10.1016/j.ajhg.2020.11.011 | |||||||
| c.3846G>C | E1282D 2D AIThe SynGAP1 missense variant E1282D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33447894-G-C). All available in silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33447894-G-C | 1 | 6.44e-7 | -3.879 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.26 | Neutral | 0.112 | Benign | 0.036 | Benign | 2.70 | Benign | 0.39 | Tolerated | 3.77 | 5 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.2699C>T | T900M 2D AIThe SynGAP1 missense variant T900M is listed in ClinVar (ID 1063691.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33443251‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443251-C-T | 14 | 8.68e-6 | -3.852 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.81 | Neutral | 0.060 | Benign | 0.016 | Benign | 2.79 | Benign | 0.08 | Tolerated | 4.32 | 4 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||
| 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 | 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 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| 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. | 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 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||
| 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 | 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 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||
| c.2623G>A | A875T 2D AIThe SynGAP1 missense variant A875T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443175‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443175-G-A | 1 | 6.20e-7 | -3.793 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.56 | Neutral | 0.972 | Probably Damaging | 0.864 | Possibly Damaging | 2.72 | Benign | 0.26 | Tolerated | 3.77 | 5 | 0 | 1 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.2650C>T | R884W 2D AIThe SynGAP1 missense variant R884W is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443202‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta (protein‑folding stability) result is available for this variant. Overall, the majority of computational predictions, including the high‑accuracy tools, indicate that R884W is most likely benign, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443202-C-T | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.151 | Likely Benign | 0.26 | Neutral | 0.995 | Probably Damaging | 0.812 | Possibly Damaging | 2.56 | Benign | 0.05 | Affected | 4.32 | 4 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||
| c.2651G>A | R884Q 2D AIThe SynGAP1 missense variant R884Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443203‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not reported, so they are unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33443203-G-A | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.42 | Neutral | 0.012 | Benign | 0.004 | Benign | 2.62 | Benign | 0.36 | Tolerated | 4.32 | 4 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.29G>C | R10P 2D AIThe SynGAP1 missense variant R10P is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33420293‑G‑C). 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) is benign; Foldetta results are unavailable. Overall, the collective evidence points to a benign effect for R10P, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33420293-G-C | 2 | 1.30e-6 | -3.772 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.05 | Neutral | 0.233 | Benign | 0.026 | Benign | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||
| 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 | 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 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.103G>A | V35I 2D AIThe SynGAP1 missense variant V35I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423512‑G‑A). 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) also indicates a benign outcome. No Foldetta stability data are 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 | Uncertain | 1 | 6-33423512-G-A | 5 | 3.10e-6 | -3.764 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.32 | Neutral | 0.672 | Possibly Damaging | 0.369 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.2300T>C | I767T 2D  AIThe SynGAP1 missense variant I767T is listed in ClinVar (ID 1044161.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, creating a single discordant prediction. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.749 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.78 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 4.12 | Benign | 0.46 | Tolerated | 3.64 | 6 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||
| c.3848C>T | P1283L 2D AIThe SynGAP1 missense variant P1283L is listed in ClinVar (ID 536994.0) as Benign and is present in gnomAD (gnomAD ID 6‑33447896‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33447896-C-T | 32 | 2.06e-5 | -3.740 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -1.04 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.76 | Benign | 0.06 | Tolerated | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.43G>A | A15T 2D AIThe SynGAP1 missense variant A15T is listed in ClinVar (ID 1925632.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33420307‑G‑A). 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”; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33420307-G-A | 4 | 2.60e-6 | -3.720 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.08 | Neutral | 0.602 | Possibly Damaging | 0.017 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
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