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.13C>G | R5G 2D  AIThe SynGAP1 missense variant R5G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as 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 | -3.639 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.169 | Likely Benign | -0.16 | Neutral | 0.013 | Benign | 0.003 | Benign | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| 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.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.1160G>T | G387V 2D  3DClick to see structure in 3D Viewer AISynGAP1 G387V is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438065-G-T). Functional prediction tools that report a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as likely benign, while the Foldetta stability assessment (combining FoldX‑MD and Rosetta) indicates a pathogenic change. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of predictions favor 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 | C2 | Uncertain | 1 | 6-33438065-G-T | 22 | 1.37e-5 | -6.199 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.390 | Likely Benign | 5.13 | Destabilizing | 1.8 | 6.44 | Destabilizing | 5.79 | Destabilizing | -0.33 | Likely Benign | -0.54 | Neutral | 0.069 | Benign | 0.077 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | -1 | -3 | 4.6 | 42.08 | 207.7 | -68.4 | -0.7 | 0.8 | -0.5 | 0.1 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This 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 significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val387 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.3386T>C | L1129P 2D  AIThe SynGAP1 missense variant L1129P 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 | 2 | -2.991 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.432 | Likely Benign | 0.27 | Neutral | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 5.44 | Benign | 0.00 | Affected | 4.32 | 4 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| 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.3308G>A | R1103H 2D  AIThe SynGAP1 missense variant R1103H is listed in ClinVar (ID 577408.0) as benign and is present in gnomAD (variant ID 6‑33443860‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of predictions support a benign impact, and this conclusion aligns with the ClinVar benign classification, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign/Likely benign | 3 | 6-33443860-G-A | 31 | 2.03e-5 | -3.622 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.97 | Neutral | 0.996 | Probably Damaging | 0.733 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.2881C>T | H961Y 2D  AIThe SynGAP1 missense variant H961Y is listed in ClinVar with an uncertain significance (ClinVar ID 862637.0) and is present in gnomAD (ID 6‑33443433‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443433-C-T | 3 | 1.86e-6 | -8.051 | Likely Pathogenic | 0.157 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.07 | Neutral | 0.716 | Possibly Damaging | 0.147 | Benign | 4.10 | Benign | 0.55 | Tolerated | 3.77 | 5 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||
| c.2291A>G | N764S 2D  AIThe SynGAP1 missense variant N764S is listed in ClinVar as Benign (ClinVar ID 1948460.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, consistent with the ClinVar classification, and there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -3.149 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.84 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.61 | Tolerated | 3.64 | 6 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.2215G>C | E739Q 2D  AIThe SynGAP1 missense variant E739Q is listed in ClinVar (ID 2429558.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, 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 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 | -2.846 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.06 | Neutral | 0.801 | Possibly Damaging | 0.339 | Benign | 2.57 | Benign | 0.00 | Affected | 4.32 | 2 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.44C>T | A15V 2D  AIThe SynGAP1 missense variant A15V is listed in ClinVar (ID 1801174.0) with an “Uncertain” status and is present in gnomAD (6‑33420308‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this 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 | 6-33420308-C-T | 1 | 6.49e-7 | -3.560 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.20 | Neutral | 0.602 | Possibly Damaging | 0.015 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| 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.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.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.2900G>T | R967L 2D  AIThe SynGAP1 missense variant R967L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443452‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for R967L, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443452-G-T | 1 | 6.20e-7 | -3.496 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.99 | Neutral | 0.959 | Probably Damaging | 0.586 | Possibly Damaging | 4.15 | Benign | 0.75 | Tolerated | 4.32 | 2 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||
| 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.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.313T>C | S105P 2D  AIThe SynGAP1 missense variant S105P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—polyPhen‑2 HumDiv and SIFT—predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.631 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.204 | Likely Benign | 0.03 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 4.00 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.1154C>T | S385L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438059‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus itself is benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of computational evidence indicates 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 | C2 | Uncertain | 2 | 6-33438059-C-T | 9 | 4.60e-5 | -6.018 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.304 | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.12 | Likely Benign | -0.26 | Likely Benign | -0.68 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.63 | Benign | 0.01 | Affected | 4.32 | 3 | -3 | -2 | 4.6 | 26.08 | 244.6 | -50.1 | 0.0 | 0.6 | -0.1 | 0.1 | 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 thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. 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.2218C>T | R740W 2D  AIThe SynGAP1 missense variant R740W is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33441683‑C‑T). Prediction tools that classify the variant as benign include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two benign vs. two pathogenic calls) and is treated as unavailable, and no Foldetta stability data are reported. Overall, the majority of conventional tools (five pathogenic vs. four benign) suggest a pathogenic impact, whereas the single high‑accuracy tool indicates benign. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 2 | 6-33441683-C-T | 6 | 3.72e-6 | -8.561 | Likely Pathogenic | 0.168 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -3.09 | Deleterious | 1.000 | Probably Damaging | 0.938 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 4.32 | 2 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||
| c.2888A>G | H963R 2D  AIThe SynGAP1 missense variant H963R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443440‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only ESM1b predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus. 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 preponderance of evidence indicates the variant is most likely benign, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443440-A-G | 8 | 4.96e-6 | -8.952 | Likely Pathogenic | 0.169 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.28 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.15 | Benign | 0.24 | Tolerated | 3.77 | 5 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||
| 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.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.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.2015C>T | T672M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441274‑C‑T). Functional prediction tools that report a benign effect include REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑2 split, and Foldetta is also inconclusive. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 2 | 6-33441274-C-T | 19 | 1.18e-5 | -9.472 | Likely Pathogenic | 0.174 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.31 | Likely Benign | 0.4 | 1.52 | Ambiguous | 0.92 | Ambiguous | 0.41 | Likely Benign | -4.34 | Deleterious | 0.993 | Probably Damaging | 0.520 | Possibly Damaging | 3.39 | Benign | 0.00 | Affected | 3.40 | 25 | -1 | -1 | 2.6 | 30.09 | 231.9 | -52.9 | 1.1 | 0.1 | 0.5 | 0.0 | X | X | Potentially Pathogenic | The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. Met672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Nevertheless, the Lys566-Glu666 salt bridge forms intermittently. This is possible because Asn669 keeps the carboxylate group of Glu666 in the vicinity through hydrogen bonding, and the hydrophobic side chain of Met stays mostly rotated away from the salt bridge. Consequently, no drastic disruption of the hydrogen-bond network that keeps the loop close to the helices occurs in the variant simulations. | ||||||||
| 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.2864C>T | S955F 2D  AISynGAP1 missense variant S955F is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33443416‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions favor a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 4 | 6-33443416-C-T | 95 | 5.89e-5 | -7.374 | In-Between | 0.176 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.73 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||
| 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.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.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.2255C>T | S752L 2D AIThe SynGAP1 missense variant S752L is listed in ClinVar with an “Uncertain” status (ClinVar ID 2143952.0) and is present in gnomAD (ID 6‑33441720‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, 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 unavailable. 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 | 2 | 6-33441720-C-T | 6 | 3.72e-6 | -3.386 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.195 | Likely Benign | -2.09 | Neutral | 0.993 | Probably Damaging | 0.641 | Possibly Damaging | 1.51 | Pathogenic | 0.01 | Affected | 3.99 | 5 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||
| 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.2765G>A | R922Q 2D AIThe SynGAP1 missense variant R922Q is listed in ClinVar as Benign (ClinVar ID 2917638.0) and is present in gnomAD (ID 6‑33443317‑G‑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, and 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 (derived from the same set of high‑confidence predictors) also as benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, 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 | Benign | 1 | 6-33443317-G-A | 7 | 4.34e-6 | -3.295 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.27 | Neutral | 0.992 | Probably Damaging | 0.736 | Possibly Damaging | 2.57 | Benign | 0.20 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| 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.3449C>T | A1150V 2D AIThe SynGAP1 missense variant A1150V is listed in ClinVar (ID 589625.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33444484‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. Foldetta, a protein‑folding stability method, did not provide a result for this variant. Overall, the majority of computational evidence indicates that A1150V is most likely benign, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33444484-C-T | 3 | 1.86e-6 | -3.648 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -2.22 | Neutral | 0.114 | Benign | 0.055 | Benign | 2.32 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| c.113C>T | P38L 2D  AIThe SynGAP1 missense variant P38L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33423522‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign 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 | 4 | 6-33423522-C-T | 8 | 4.96e-6 | -2.469 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -2.56 | Deleterious | 0.983 | Probably Damaging | 0.931 | Probably Damaging | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||
| c.1667A>G | N556S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N556S (ClinVar ID 941099.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438910‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign effect. No other high‑accuracy or folding‑stability methods provide additional evidence. Overall, the majority of predictions support a benign impact, which does not contradict the ClinVar Uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438910-A-G | 3 | 1.86e-6 | -6.576 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.449 | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.14 | Likely Benign | 0.33 | Likely Benign | 0.16 | Likely Benign | -3.60 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.22 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 1 | 1 | 2.7 | -27.03 | 198.8 | 31.0 | 0.0 | 0.0 | -0.5 | 0.2 | X | Potentially Benign | Asn556 is located on the outer surface of an α-helix (res. Ala533-Val560). The carboxamide group of Asn556 forms hydrogen bonds with nearby residues such as Lys553 and Cys552. It also forms a hydrogen bond with the backbone carbonyl group of Cys552, which weakens the α-helix integrity. In the variant simulations, the hydroxyl group of Ser556 forms a more stable hydrogen bond with the backbone carbonyl oxygen of the same helix residue, Cys552, compared to Asn556 in the WT. Serine has a slightly lower propensity to reside in an α-helix than asparagine, which may exacerbate the negative effect on the α-helix integrity. However, the residue swap does not cause negative structural effects during the simulations. | |||||||||
| c.2669G>A | R890H 2D AIThe SynGAP1 missense variant R890H is listed in ClinVar as a benign alteration (ClinVar ID 1037885.0) and is observed in gnomAD (6‑33443221‑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, and no tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” while Foldetta’s protein‑folding stability analysis is unavailable. Overall, the computational evidence strongly 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 | 6-33443221-G-A | 19 | 1.18e-5 | -3.600 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.29 | Neutral | 0.254 | Benign | 0.134 | Benign | 3.97 | Benign | 0.15 | Tolerated | 4.32 | 4 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.3923G>A | R1308H 2D AIThe SynGAP1 missense variant R1308H (ClinVar ID 1996244.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33451797‑G‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessment shows AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive, and Foldetta results are unavailable. Consequently, the overall computational evidence leans toward a pathogenic interpretation, but the presence of a single high‑accuracy benign prediction and the inconclusive SGM Consensus leave the variant’s effect uncertain. This computational assessment does not contradict the ClinVar status, which remains Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33451797-G-A | 3 | 1.86e-6 | -3.586 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.319 | Likely Benign | -3.12 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
| 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.2420A>G | Y807C 2D  AIThe SynGAP1 missense variant Y807C is listed in ClinVar with an “Uncertain” status (ClinVar ID 2119812.0) and is present in gnomAD (ID 6‑33442972‑A‑G). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation, whereas AlphaMissense‑Optimized alone suggests benign. The variant is most likely pathogenic based on the collective evidence, and this conclusion is not contradicted by the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | Uncertain | 1 | 6-33442972-A-G | 1 | 6.20e-7 | -7.228 | In-Between | 0.204 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -3.89 | Deleterious | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||
| c.3308G>T | R1103L 2D AIThe SynGAP1 missense variant R1103L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443860‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome (3 benign vs. 1 pathogenic votes). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33443860-G-T | -2.330 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.35 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| 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.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.3002T>C | L1001P 2D AIThe SynGAP1 missense variant L1001P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.071 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.02 | Neutral | 0.966 | Probably Damaging | 0.690 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 4.32 | 4 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.1131G>A | M377I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I (ClinVar ID 3803473.0, status = Uncertain) is present in gnomAD (ID = 6‑33438036‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the computational evidence strongly favors a benign classification, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438036-G-A | 1 | 6.23e-7 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.227 | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||
| c.2246G>A | R749Q 2D AIThe SynGAP1 missense variant R749Q is listed in ClinVar (ID 793884.0) as Benign and is present in gnomAD (6‑33441711‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a Likely Benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence—including high‑accuracy predictions—supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33441711-G-A | 4 | 2.48e-6 | -3.069 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.00 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 2 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| 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.3048C>A | D1016E 2D  AIThe SynGAP1 missense variant D1016E is reported in ClinVar (ID 3803472.0) as benign and is present in gnomAD (variant ID 6‑33443600‑C‑A). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar benign classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | 6-33443600-C-A | 2 | 1.24e-6 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.3314G>A | R1105Q 2D AIThe SynGAP1 missense variant R1105Q is listed in ClinVar (ID 1803693.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443866‑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 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 further support this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, 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 | 2 | 6-33443866-G-A | 3 | 1.96e-6 | -3.666 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.21 | Neutral | 0.958 | Probably Damaging | 0.194 | Benign | 2.50 | Benign | 0.16 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.1045C>T | P349S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P349S missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, predict a pathogenic effect. Thus, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.654 | In-Between | 0.217 | Likely Benign | Likely Benign | 0.277 | Likely Benign | 1.92 | Ambiguous | 0.1 | 2.28 | Destabilizing | 2.10 | Destabilizing | 0.87 | Ambiguous | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.66 | Pathogenic | 0.06 | Tolerated | 3.37 | 25 | 1 | -1 | 0.8 | -10.04 | 194.9 | -18.1 | -0.1 | 0.0 | 0.2 | 0.1 | X | X | Potentially Pathogenic | The cyclic pyrrolidine side chain of Pro349, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), allows the strand to end and make a tight turn before a short α helical section within a loop connecting to another β strand (res. Thr359-Pro364). In the variant simulations, the hydroxyl group of Ser349 forms a hydrogen bond with the backbone amide group of Ala351 in the short helical section. Conversely, the backbone amide group of Ser349 (absent in proline) does not form any intra-protein hydrogen bonds. However, the β strand end connects to the α helical section in a more stable and consistent manner compared to the WT. Although the residue swap does not cause major adverse effects on the protein structure in the simulations, it is possible that the tight turn at the β strand end could not be created during folding without the presence of proline. | |||||||||||
| c.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.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.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.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.3424T>C | S1142P 2D AIThe SynGAP1 missense variant S1142P is listed in ClinVar (ID 2747352.0) as Benign and is present in gnomAD (variant ID 6‑33444459‑T‑C). 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, 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, 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 | Likely Benign | 1 | 6-33444459-T-C | 1 | 6.20e-7 | -2.713 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.19 | Neutral | 0.918 | Possibly Damaging | 0.761 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 4.32 | 4 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.458C>A | T153N 2D AIThe SynGAP1 missense variant T153N is listed in ClinVar (ID 984906.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | -0.739 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.88 | Neutral | 0.888 | Possibly Damaging | 0.537 | Possibly Damaging | 4.23 | Benign | 0.81 | Tolerated | 3.61 | 5 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||
| 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.314C>T | S105L 2D AIThe SynGAP1 missense variant S105L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432179‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy methods both support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33432179-C-T | 4 | 2.48e-6 | -3.710 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.52 | Neutral | 0.828 | Possibly Damaging | 0.048 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||
| 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.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.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.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.1851G>T | E617D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617D is listed in ClinVar with an uncertain significance (ID 2584916.0) and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence supports a benign classification, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.322 | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||
| 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.2243T>G | L748R 2D  AIThe SynGAP1 missense variant L748R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441708‑T‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33441708-T-G | 3 | 1.86e-6 | -3.331 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.67 | Neutral | 0.912 | Possibly Damaging | 0.448 | Possibly Damaging | 2.73 | Benign | 0.02 | Affected | 4.32 | 2 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||
| c.3307C>T | R1103C 2D AISynGAP1 missense variant R1103C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443859‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized reports a benign outcome, while Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33443859-C-T | 6 | 3.92e-6 | -2.440 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -3.01 | Deleterious | 0.996 | Probably Damaging | 0.787 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.886T>G | S296A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296A (ClinVar ID 469166.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or neutral. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign effect. No evidence from the available tools suggests a deleterious impact. Therefore, the variant is most likely benign, and this conclusion is consistent with its ClinVar status of Uncertain rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | -6.847 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.209 | Likely Benign | 0.50 | Ambiguous | 0.3 | -0.26 | Likely Benign | 0.12 | Likely Benign | 0.35 | Likely Benign | -1.79 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.97 | Pathogenic | 0.65 | Tolerated | 3.40 | 16 | 1 | 1 | 2.6 | -16.00 | 182.5 | 26.6 | -0.2 | 0.1 | -0.5 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations. | |||||||||||
| c.53A>G | Y18C 2D AIThe SynGAP1 missense variant Y18C is listed in ClinVar with an uncertain significance (ClinVar ID 1967233.0) and is present in gnomAD (ID 6‑33420317‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for Y18C, 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 | 6-33420317-A-G | 44 | 2.88e-5 | -2.658 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.56 | Neutral | 0.872 | Possibly Damaging | 0.206 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||
| c.1502T>C | I501T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and premPS, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -5.996 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.362 | Likely Benign | 2.40 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.11 | Destabilizing | 1.57 | Destabilizing | -3.48 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.44 | Benign | 0.16 | Tolerated | 3.37 | 35 | 0 | -1 | -5.2 | -12.05 | 214.5 | 26.9 | 0.0 | 0.0 | 0.5 | 0.0 | X | Potentially Pathogenic | Ile501 is located near a hinge in the middle of an α-helix (res. Leu489-Glu519). The sec-butyl side chain of Ile501 is hydrophobically packed with other residues in the inter-helix space (e.g., Leu500, Tyr497, Phe679) in the WT simulations. In the variant simulations, the hydroxyl group of Thr501 forms a hydrogen bond with the backbone atoms of Tyr497 on the same α-helix, which may weaken the α-helix integrity. Additionally, the polar hydroxyl group of Thr501 is not suitable for the hydrophobic inter-helix space, and thus, the residue swap could affect protein folding. However, Ile501 is followed by Gly502, which facilitates a hinge in the middle of the α-helix, making further weakening caused by Thr501 unlikely to be harmful to the α-helix integrity. | |||||||||||
| c.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.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.2837G>A | G946E 2D  AIThe SynGAP1 missense variant G946E is listed in ClinVar (ID 1299783.0) as benign and is present in gnomAD (6‑33443389‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, SIFT, and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 3 | 6-33443389-G-A | 13 | 8.05e-6 | -8.793 | Likely Pathogenic | 0.257 | Likely Benign | Likely Benign | 0.341 | Likely Benign | -0.51 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 4.58 | Benign | 0.00 | Affected | 4.32 | 4 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||
| 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.3631A>G | M1211V 2D  AIThe SynGAP1 missense variant M1211V is listed in ClinVar as Benign (ClinVar ID 3674914.0) and is present in gnomAD (ID 6‑33446623‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Benign | 1 | 6-33446623-A-G | 3 | 1.86e-6 | -2.101 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.412 | Likely Benign | -0.29 | Neutral | 0.932 | Possibly Damaging | 0.949 | Probably Damaging | 5.43 | Benign | 0.72 | Tolerated | 3.77 | 5 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||
| c.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (variant ID 6‑33438468‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic impact. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” status; thus the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| c.502C>T | H168Y 2D AIThe SynGAP1 missense variant H168Y is listed in ClinVar (ID 956914.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -8.914 | Likely Pathogenic | 0.264 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.53 | Neutral | 0.192 | Benign | 0.062 | Benign | 4.18 | Benign | 0.01 | Affected | 4.32 | 3 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 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.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.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.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.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.777 | Likely Pathogenic | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | |||||||||
| c.1730C>G | A577G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577G is listed in ClinVar as Benign (ClinVar ID 1010280.0) and is present in gnomAD (ID 6‑33440782‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy methods give a benign verdict: AlphaMissense‑Optimized is benign, the SGM‑Consensus is Likely Benign, and Foldetta is uncertain. Overall, the majority of reliable predictions support a benign impact, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Benign/Likely benign | 2 | 6-33440782-C-G | 1 | 6.20e-7 | -5.717 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.443 | Likely Benign | 0.83 | Ambiguous | 0.0 | 1.02 | Ambiguous | 0.93 | Ambiguous | 0.86 | Ambiguous | -1.84 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.31 | Pathogenic | 0.31 | Tolerated | 3.37 | 34 | 1 | 0 | -2.2 | -14.03 | 158.7 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. The introduced residue, glycine, is known as an “α-helix breaker.” However, the residue swap caused only minor helix shortening in one of the replica simulations for the variant system. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | ||||||||
| c.1606T>G | L536V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536V is listed in ClinVar (ID 1690714.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.014 | Likely Pathogenic | 0.269 | Likely Benign | Likely Benign | 0.586 | Likely Pathogenic | 1.25 | Ambiguous | 0.3 | 1.22 | Ambiguous | 1.24 | Ambiguous | 1.20 | Destabilizing | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.09 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.7 | 26.4 | 0.2 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects. | |||||||||||
| c.3983G>A | R1328Q 2D AIThe SynGAP1 missense variant R1328Q is listed in ClinVar (ID 1805359.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451857‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 3 | 6-33451857-G-A | 35 | 1.49e-4 | -2.921 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.799 | Possibly Damaging | 0.098 | Benign | 4.12 | Benign | 0.03 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.2216A>T | E739V 2D  AIThe SynGAP1 missense variant E739V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.136 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.86 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | 4.32 | 2 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||
| 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.2339C>G | S780C 2D  AIThe SynGAP1 missense variant S780C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442891‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome; ESM1b is inconclusive and therefore treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are not reported and thus unavailable. Based on the collective predictions, the variant is most likely benign, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 4 | 6-33442891-C-G | 16 | 9.94e-6 | -7.603 | In-Between | 0.278 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.41 | Neutral | 0.065 | Benign | 0.043 | Benign | 2.59 | Benign | 0.10 | Tolerated | 3.64 | 6 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||||
| 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.815G>A | R272Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R272Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437720‑G‑A). Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and PROVEAN. Those that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; and Foldetta predicts benign. With the majority of high‑accuracy tools supporting a benign effect, the variant is most likely benign, which does not contradict its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 2 | 6-33437720-G-A | 14 | 8.67e-6 | -9.559 | Likely Pathogenic | 0.286 | Likely Benign | Likely Benign | 0.321 | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.15 | Likely Benign | 0.44 | Likely Benign | 1.00 | Destabilizing | -1.81 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.88 | Pathogenic | 0.03 | Affected | 3.38 | 19 | 1 | 1 | 1.0 | -28.06 | 255.7 | 52.9 | 0.0 | 0.0 | -0.2 | 0.1 | X | Uncertain | The guanidinium group of Arg272, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), is stably maintained in an upright and outward position via stacking with the indole ring of the Trp362 side chain in another β strand (res. Thr359-Pro364). In the WT simulations, Arg272 forms hydrogen bonds with the glycine-rich Ω loop residues (res. Val365-Pro398, e.g., Gly380) and creates a salt bridge with the carboxylate group of the Asp304 side chain.In the variant simulations, the carboxamide group of the Gln272 side chain does not stack with the indole ring of Trp362 as stably as the guanidinium group of Arg272 in the WT. Consequently, the Gln272 side chain is freer to interact with the loop residues than Arg272, potentially negatively affecting the dynamic SynGAP-membrane association. Additionally, Arg272 faces the RasGTPase interface, so the residue swap could impact the SynGAP-Ras complex formation and GTPase activation. | |||||||||
| c.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.2502G>C | M834I 2D AIThe SynGAP1 missense variant M834I is listed in ClinVar (ID 3007819.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the collective predictions indicate that M834I is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.3323G>T | S1108I 2D  AIThe SynGAP1 missense variant S1108I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443875‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no reported result for this variant. Overall, the balance of evidence (five benign versus four pathogenic predictions) suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33443875-G-T | -3.666 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -3.73 | Deleterious | 0.971 | Probably Damaging | 0.604 | Possibly Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| c.2719A>T | S907C 2D AIThe SynGAP1 missense variant S907C is listed in ClinVar as Benign (ClinVar ID 1502069.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification and indicating no contradiction with the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 1 | -6.685 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.34 | Neutral | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| 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.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.1957C>G | L653V 2D AIThe SynGAP1 missense variant L653V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and premPS, while ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -7.050 | In-Between | 0.301 | Likely Benign | Likely Benign | 0.146 | Likely Benign | 3.28 | Destabilizing | 0.3 | 2.18 | Destabilizing | 2.73 | Destabilizing | 1.32 | Destabilizing | -2.25 | Neutral | 0.227 | Benign | 0.039 | Benign | 3.28 | Benign | 0.08 | Tolerated | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||
| c.2669G>C | R890P 2D AIThe SynGAP1 missense variant R890P is listed in ClinVar (ID 575680.0) as Benign and is present in gnomAD (6‑33443221‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar status, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Likely Benign | 2 | 6-33443221-G-C | 28 | 1.74e-5 | -1.931 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -1.21 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 4.02 | Benign | 0.28 | Tolerated | 4.32 | 4 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||
| c.136C>T | P46S 2D AIThe SynGAP1 missense variant P46S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.338 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.60 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2147G>A | R716Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716Q is listed in ClinVar with an uncertain significance (ClinVar ID 411585.0) and is present in gnomAD (ID 6‑33441612‑G‑A). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b, while premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 2 | 6-33441612-G-A | 4 | 2.48e-6 | -8.338 | Likely Pathogenic | 0.308 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.47 | Likely Benign | 0.23 | Likely Benign | 0.58 | Ambiguous | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.50 | 9 | 1 | 1 | 1.0 | -28.06 | 250.0 | 48.9 | 0.0 | 0.0 | -0.5 | 0.0 | X | Uncertain | The guanidinium group of Arg716, located on the outer surface of an α-helix (res. Leu714-Arg726), forms a salt bridge with the carboxylate group of Asp720. In the variant simulations, the carboxamide group of Gln716 also forms a hydrogen bond with the carboxylate group of Asp720, although this bond is weaker than the Arg716 salt bridge in the WT. Overall, no adverse effects on the protein structure are observed in the simulations. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||
| c.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.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.3152G>A | G1051D 2D  AISynGAP1 missense variant G1051D is listed in ClinVar as Benign and is present in gnomAD (variant ID 6‑33443704‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Benign | 1 | 6-33443704-G-A | 2 | 1.24e-6 | -9.379 | Likely Pathogenic | 0.311 | Likely Benign | Likely Benign | 0.445 | Likely Benign | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||
| c.667A>G | T223A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223A is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33435518‑A‑G). Functional prediction tools that agree on a benign effect include FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and PROVEAN. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.574 | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||
| c.4013G>A | R1338Q 2D AIThe SynGAP1 missense variant R1338Q is listed in ClinVar (ID 450879.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451887‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports it as “Likely Benign.” In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33451887-G-A | 12 | 8.40e-6 | -3.494 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.87 | Neutral | 0.896 | Possibly Damaging | 0.194 | Benign | 3.81 | Benign | 0.02 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.380G>A | R127Q 2D AIThe SynGAP1 missense variant R127Q (ClinVar ID 2898917.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33432245‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar Uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33432245-G-A | 6 | 3.72e-6 | -1.711 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.04 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.04 | Benign | 0.02 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| 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.2343G>A | M781I 2D AIThe SynGAP1 missense variant M781I is listed in ClinVar (ID 2802065.0) as Benign and is not reported in gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions strongly support a benign effect, consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| 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.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.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.1586T>C | I529T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification—there is no contradiction between the predictions and the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -0.539 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.343 | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.16 | Likely Benign | 0.19 | Likely Benign | 0.17 | Likely Benign | 0.24 | Neutral | 0.872 | Possibly Damaging | 0.820 | Possibly Damaging | -1.23 | Pathogenic | 0.55 | Tolerated | 3.37 | 35 | 0 | -1 | -5.2 | -12.05 | 207.2 | 29.8 | 0.2 | 0.0 | 0.2 | 0.1 | X | Potentially Benign | Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 0.730 | Likely Pathogenic | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | ||||||||
| c.2245C>T | R749W 2D AIThe SynGAP1 missense variant R749W is listed in ClinVar as benign and is observed in gnomAD (ID 6‑33441710‑C‑T). Prediction tools that classify the variant as benign include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta stability analysis is unavailable. Overall, the majority of evidence, especially from high‑confidence methods, supports a benign effect. This consensus aligns with the ClinVar designation, so there is no contradiction between the predictions and the reported clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 1 | 6-33441710-C-T | 3 | 1.86e-6 | -7.647 | In-Between | 0.338 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.62 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 2 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||
| 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.1622C>G | A541G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438865-C-G | 2 | 1.24e-6 | -7.233 | In-Between | 0.341 | Ambiguous | Likely Benign | 0.421 | Likely Benign | 0.67 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.81 | Ambiguous | 0.76 | Ambiguous | -1.48 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.57 | Tolerated | 3.37 | 35 | 1 | 0 | -2.2 | -14.03 | 170.1 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted. | |||||||||
| c.1121C>A | S374Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S374Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, whereas polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. Uncertain calls come from FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta likewise yields an uncertain stability change. Overall, the majority of available predictions favor a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.774 | In-Between | 0.344 | Ambiguous | Likely Benign | 0.310 | Likely Benign | 0.71 | Ambiguous | 1.2 | 0.66 | Ambiguous | 0.69 | Ambiguous | -0.02 | Likely Benign | -1.18 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 5.41 | Benign | 0.01 | Affected | 4.32 | 13 | -3 | -2 | -0.5 | 76.10 | 237.3 | -76.9 | 0.5 | 0.4 | 0.5 | 0.3 | Uncertain | Ser374 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus, large and relatively hydrophobic residues like tyrosine are rarely tolerated. Additionally, the hydroxyl group of Tyr374 frequently forms various hydrogen bonds with other loop residues in the variant simulations. Although no negative structural effects are observed in the variant simulations, Tyr374 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||||
| c.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.2105A>G | Q702R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q702R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that remain inconclusive are Rosetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to equal benign and pathogenic signals. Overall, the majority of available predictions lean toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | -7.894 | In-Between | 0.348 | Ambiguous | Likely Benign | 0.294 | Likely Benign | -0.31 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.16 | Likely Benign | 0.13 | Likely Benign | -3.14 | Deleterious | 0.909 | Possibly Damaging | 0.889 | Possibly Damaging | 3.43 | Benign | 0.02 | Affected | 3.47 | 10 | 1 | 1 | -1.0 | 28.06 | 270.3 | -52.9 | 0.0 | 0.0 | 0.0 | 0.1 | X | Potentially Pathogenic | The carboxamide side chain of Gln702 is located at the end and outer surface of an α-helix (res. Leu685-Gln702), where it does not directly form hydrogen bonds with any residues in the WT simulations. In the variant simulations, the positively charged guanidinium group of Arg702 forms a salt bridge with the negatively charged carboxylate group of Glu698 on the same helix and/or hydrogen bonds with the backbone carbonyl group of Ala438 on an opposite α-helix (res. Tyr428-Glu436). Consequently, the residue swap could strengthen the tertiary structure assembly, which could have either positive or negative effects on its function. | ||||||||||||
| c.3161G>A | G1054D 2D AISynGAP1 missense variant G1054D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -10.385 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.279 | Likely Benign | -0.26 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.07 | Benign | 0.37 | Tolerated | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||
| c.3184G>A | G1062R 2D  AIThe SynGAP1 missense variant G1062R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443736‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, polyPhen‑2 HumVar, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443736-G-A | 7 | 4.35e-6 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.899C>T | S300F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S300F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The remaining tool, AlphaMissense‑Default, gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, while two high‑accuracy methods support a benign effect. Thus, the variant is most likely pathogenic based on the current computational evidence, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -10.222 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -0.29 | Likely Benign | 0.4 | 0.16 | Likely Benign | -0.07 | Likely Benign | 0.04 | Likely Benign | -2.66 | Deleterious | 0.975 | Probably Damaging | 0.596 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.47 | 19 | -3 | -2 | 3.6 | 60.10 | 233.6 | -67.6 | -0.1 | 0.0 | 0.4 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl group of the Ser300 side chain, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), hydrogen bonds with the guanidinium group of Arg299 and the backbone amide group and side chain of Ser302. Thus, in the WT simulations, it contributes to the β hairpin stability. In the variant simulations, the phenol ring of Phe300 cannot form any side chain-related hydrogen bonds, and Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 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.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.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.1322T>C | V441A 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V441A is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33438227‑T‑C). Consensus from most in silico predictors favors a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all report benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and ESM1b, while premPS and AlphaMissense‑Default remain uncertain. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 2 | 6-33438227-T-C | 3 | 1.86e-6 | -9.439 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.053 | Likely Benign | -0.14 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.10 | Likely Benign | 0.95 | Ambiguous | -2.92 | Deleterious | 0.513 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.93 | Tolerated | 3.37 | 29 | 0 | 0 | -2.4 | -28.05 | 195.0 | 44.6 | 0.0 | 0.1 | 0.5 | 0.0 | X | X | Uncertain | The iso-propyl side chain of Val441, located on the outer surface of an α helix (res. Asn440-Thr458), does not interact with other residues in the WT simulations. In the variant simulations, the methyl side chain of Ala441 is similarly hydrophobic and does not form any interactions on the outer helix surface. Although the residue swap does not negatively affect the protein structure based on the simulations, it is noteworthy that the residue faces the RasGTPase interface. Thus, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||
| c.526A>G | S176G 2D AIThe SynGAP1 missense variant S176G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435168‑A‑G). Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all report a benign effect. No tool predicts pathogenicity. Two predictors are inconclusive: ESM1b and AlphaMissense‑Default, which are grouped under uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains uncertain, and Foldetta stability analysis is unavailable. Overall, the computational evidence overwhelmingly favors a benign impact, which does not contradict the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33435168-A-G | 1 | 6.20e-7 | -7.541 | In-Between | 0.360 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.08 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.08 | Benign | 0.22 | Tolerated | 3.54 | 6 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||
| c.1354G>A | V452I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.218 | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||
| c.1402A>G | M468V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools, premPS and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | -9.461 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.570 | Likely Pathogenic | 2.69 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.45 | Destabilizing | 0.89 | Ambiguous | -1.66 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.21 | Pathogenic | 0.08 | Tolerated | 3.37 | 31 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||
| c.2729G>C | G910A 2D  AIThe SynGAP1 missense variant G910A is listed in ClinVar with an “Uncertain” status (ClinVar ID 2091237.0) and is present in gnomAD (6‑33443281‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. The remaining predictions are uncertain: AlphaMissense‑Default is inconclusive, while the SGM‑Consensus (majority vote from 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 results are unavailable. 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 | 6-33443281-G-C | 1 | 6.20e-7 | -3.587 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.209 | Likely Benign | -1.43 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.78 | Benign | 0.10 | Tolerated | 3.77 | 5 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||
| c.1154C>G | S385W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385W is listed in ClinVar as Benign (ClinVar ID 218691.0) and is present in gnomAD (ID 6‑33438059‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus as Benign, and Foldetta as Uncertain. Taken together, the majority of evidence points to a benign impact, which aligns with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Benign | 1 | 6-33438059-C-G | -9.353 | Likely Pathogenic | 0.362 | Ambiguous | Likely Benign | 0.373 | Likely Benign | 0.53 | Ambiguous | 0.2 | 0.69 | Ambiguous | 0.61 | Ambiguous | 0.00 | Likely Benign | -0.84 | Neutral | 0.986 | Probably Damaging | 0.968 | Probably Damaging | 4.63 | Benign | 0.00 | Affected | 4.32 | 3 | -2 | -3 | -0.1 | 99.14 | 260.4 | -71.2 | 0.5 | 1.3 | 0.7 | 0.4 | 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 thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. 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. | 10.1016/j.ajhg.2020.11.011 | |||||||||||
| c.958G>C | V320L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437863‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the 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. | C2 | Uncertain | 1 | 6-33437863-G-C | 6 | 3.72e-6 | -6.207 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.26 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | -1.02 | Neutral | 0.900 | Possibly Damaging | 0.373 | Benign | 1.78 | Pathogenic | 0.92 | Tolerated | 3.38 | 23 | 2 | 1 | -0.4 | 14.03 | 245.8 | -10.2 | 0.3 | 0.9 | 0.1 | 0.3 | X | Potentially Benign | The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations. | |||||||||
| c.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.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.3175G>A | G1059R 2D AIThe SynGAP1 missense variant G1059R is listed in ClinVar with an “Uncertain” significance and is present in the gnomAD database (ID 6‑33443727‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a benign prediction (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus also benign; Foldetta’s protein‑folding stability analysis is unavailable for this variant. Overall, the collective 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. | Uncertain | 1 | 6-33443727-G-A | 68 | 4.23e-5 | -8.452 | Likely Pathogenic | 0.376 | Ambiguous | Likely Benign | 0.333 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| 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.3154G>A | G1052R 2D AISynGAP1 missense variant G1052R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status but provides additional support toward a likely benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||
| c.1231A>G | I411V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411V is reported in ClinVar as benign (ClinVar ID 1654508.0) and is not found 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). Two tools predict a pathogenic outcome: PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are AlphaMissense‑Default, FoldX, Rosetta, premPS, and Foldetta. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. Overall, the preponderance of evidence points to a benign effect for I411V, which is consistent 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 | Likely Benign | 1 | -6.290 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.212 | Likely Benign | 0.74 | Ambiguous | 0.0 | 0.82 | Ambiguous | 0.78 | Ambiguous | 0.99 | Ambiguous | -0.86 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.90 | Benign | 0.27 | Tolerated | 3.38 | 28 | 4 | 3 | -0.3 | -14.03 | 233.3 | 28.2 | -0.2 | 0.0 | -0.2 | 0.0 | X | Potentially Benign | The sec-butyl side chain of Ile411, located in the hydrophobic space between an anti-parallel β sheet strand (res. Pro398-Ile411) and an α helix (res. Asp684-Gln702), packs against multiple residues (e.g., Met409, Arg259). In the variant simulations, the side chain of Val411 is able to favorably fill the same hydrophobic niche despite its slightly smaller size. In short, the residue swap has no apparent negative effect on the structure based on the simulations. | |||||||||||
| c.961C>T | R321C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Conflicting | 2 | 6-33437866-C-T | 9 | 5.58e-6 | -10.025 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.495 | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | 0.57 | Ambiguous | 0.18 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 23 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||
| c.1136C>G | S379W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 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 tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp379 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.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.896G>A | R299H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299H is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437801‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between pathogenic and uncertain calls. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Conflicting | 2 | 6-33437801-G-A | 10 | 6.20e-6 | -7.731 | In-Between | 0.388 | Ambiguous | Likely Benign | 0.238 | Likely Benign | 3.97 | Destabilizing | 1.0 | 0.94 | Ambiguous | 2.46 | Destabilizing | 1.41 | Destabilizing | -3.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 19 | 2 | 0 | 1.3 | -19.05 | 211.2 | 72.5 | -0.1 | 0.2 | -0.2 | 0.3 | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | |||||||||
| c.910G>A | D304N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D304N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -6.194 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.345 | Likely Benign | 0.30 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | -4.18 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.81 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||
| c.3395C>A | S1132Y 2D AIThe SynGAP1 missense variant S1132Y is listed in ClinVar as a benign alteration (ClinVar ID 845357.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). 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 stability analysis is unavailable. Overall, the majority of 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 | Likely Benign | 1 | -5.894 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.401 | Likely Benign | -1.76 | Neutral | 0.500 | Possibly Damaging | 0.208 | Benign | 5.40 | Benign | 0.09 | Tolerated | 4.32 | 4 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| 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.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.277C>G | R93G 2D AIThe SynGAP1 missense variant R93G is listed in ClinVar (ID 2504251.0) with an “Uncertain” clinical significance 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‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from the same set of predictors) labels it “Likely Benign”; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that R93G 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 | Uncertain | 1 | -2.674 | Likely Benign | 0.400 | Ambiguous | Likely Benign | 0.093 | Likely Benign | -1.69 | Neutral | 0.103 | Benign | 0.019 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.2668C>T | R890C 2D AIThe SynGAP1 missense variant R890C is listed in ClinVar as benign and is present in gnomAD (6-33443220-C‑T). Functional prediction tools show mixed results: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence leans toward a benign effect, 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. | Benign | 1 | 6-33443220-C-T | 9 | 5.58e-6 | -5.786 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.200 | Likely Benign | -3.38 | Deleterious | 1.000 | Probably Damaging | 0.971 | Probably Damaging | 3.94 | Benign | 0.04 | Affected | 4.32 | 4 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.3368G>A | G1123D 2D AISynGAP1 missense variant G1123D is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443920‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and ESM1b. AlphaMissense‑Default remains uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus also benign, while Foldetta provides no data. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33443920-G-A | 2 | 1.33e-6 | -10.321 | Likely Pathogenic | 0.405 | Ambiguous | Likely Benign | 0.360 | Likely Benign | -0.78 | Neutral | 0.500 | Possibly Damaging | 0.157 | Benign | 4.34 | Benign | 0.19 | Tolerated | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||
| c.1408A>C | M470L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is listed in ClinVar as benign (ClinVar ID 536996.0) and is present in gnomAD (variant ID 6‑33438440‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No definitive folding‑stability change is reported by FoldX or Rosetta individually. Overall, the majority of predictive algorithms favor a pathogenic effect, directly contradicting the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33438440-A-C | 1 | 6.20e-7 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.678 | Likely Pathogenic | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | ||||||||
| c.603T>A | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (ClinVar ID 3004688.0) is classified as **Benign** in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as **Benign**, the SGM‑Consensus as **Likely Benign**, and Foldetta as **Uncertain**. Taken together, the overwhelming majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation. Thus, the variant is most likely benign, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | Benign | 1 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||
| c.603T>G | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (gnomAD ID 6‑33435245‑T‑G) is listed in ClinVar with an uncertain significance. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign. Only polyPhen‑2 HumDiv predicts pathogenicity, while Rosetta, Foldetta, and AlphaMissense‑Default remain inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “likely benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta is inconclusive. Taken together, the preponderance of evidence points to a benign impact, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | Conflicting | 2 | 6-33435245-T-G | 20 | 1.24e-5 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||
| c.3862A>G | K1288E 2D  AISynGAP1 missense variant K1288E is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33447910‑A‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this change. Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than a clear benign classification. Thus, the variant is most likely pathogenic, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33447910-A-G | 5 | 3.22e-6 | -2.751 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -3.27 | Deleterious | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||
| c.667A>T | T223S 2D  3DClick to see structure in 3D Viewer AISynGAP1 T223S is listed in ClinVar as a variant of uncertain significance and is present in the gnomAD database (ID 6‑33435518‑A‑T). Functional prediction tools that reach consensus classify the variant as benign: FoldX, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity include REVEL, PROVEAN, and SIFT. Predictions that are inconclusive or uncertain are Rosetta, premPS, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic calls. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Conflicting | 2 | 6-33435518-A-T | 3 | 1.86e-6 | -7.714 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.535 | Likely Pathogenic | 0.26 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.38 | Likely Benign | 0.62 | Ambiguous | -2.86 | Deleterious | 0.421 | Benign | 0.058 | Benign | 5.80 | Benign | 0.02 | Affected | 3.41 | 13 | 1 | 1 | -0.1 | -14.03 | 200.7 | 17.3 | -0.2 | 0.2 | 0.0 | 0.0 | X | Uncertain | The introduced residue Ser223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Its hydroxyl group forms hydrogen bonds with nearby residues Thr228 and Lys207 in the variant simulations, similar to the hydroxyl group of Thr223 in the WT simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and may prevent it from unfolding. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.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.2249G>A | G750E 2D AISynGAP1 missense variant G750E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -2.618 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -2.27 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.99 | 5 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||
| c.3125A>G | Q1042R 2D AIThe SynGAP1 missense variant Q1042R is listed in ClinVar (ID 2662705.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443677‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, the majority of evidence supports a benign impact for Q1042R, 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 | 2 | 6-33443677-A-G | 2 | 1.24e-6 | -2.928 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.300 | Likely Benign | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.120 | Benign | 5.48 | Benign | 0.12 | Tolerated | 3.77 | 5 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||
| c.1417G>A | V473I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.203 | Likely Benign | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||
| c.2349G>A | M783I 2D AIThe SynGAP1 missense variant M783I is listed in ClinVar as a benign alteration (ClinVar ID 3618151.0) and is present in the gnomAD database (gnomAD ID 6‑33442901‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a likely benign effect. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly suggests that the variant is most likely benign, in agreement with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33442901-G-A | 6 | 3.72e-6 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1752C>G | I584M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant I584M is listed in ClinVar with an uncertain significance (ClinVar ID 1301269.0) and is present in gnomAD (6‑33440804‑C‑G). Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized, whereas pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the majority of tools favor pathogenicity, and the high‑accuracy consensus leans pathogenic, indicating the variant is most likely pathogenic, 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 Pathogenic | GAP | Uncertain | 2 | 6-33440804-C-G | 1 | 6.20e-7 | -10.119 | Likely Pathogenic | 0.419 | Ambiguous | Likely Benign | 0.478 | Likely Benign | 0.11 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.29 | Likely Benign | 1.16 | Destabilizing | -2.62 | Deleterious | 0.983 | Probably Damaging | 0.925 | Probably Damaging | -1.25 | Pathogenic | 0.12 | Tolerated | 3.37 | 34 | 2 | 1 | -2.6 | 18.03 | 247.5 | -20.3 | -0.1 | 0.3 | -0.1 | 0.1 | X | Potentially Benign | A hydrophobic residue, Ile584, located in an α helix (res. Glu582-Met603), is swapped for another hydrophobic residue, Met584. The sec-butyl hydrocarbon side chain of Ile584 packs hydrophobically with residues in an inter-helix hydrophobic space (e.g., Leu588, Met477, Val473, and Ile483).In the variant simulations, the thioether hydrophobic side chain of Met584 maintains similar interactions as Ile584 in the WT, as it is roughly the same size and fits well within the hydrophobic space. Thus, the residue swap does not appear to cause any negative effects on the protein structure. | ||||||||
| c.2111G>A | S704N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704N is listed in ClinVar as benign (ClinVar ID 962301.0) and is present in gnomAD (ID 6‑33441370‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus all report benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the predictions support a benign classification, consistent with the ClinVar status and with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Benign/Likely benign | 3 | 6-33441370-G-A | 27 | 1.67e-5 | -5.917 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.058 | Likely Benign | 0.48 | Likely Benign | 0.1 | -0.12 | Likely Benign | 0.18 | Likely Benign | 0.54 | Ambiguous | -0.49 | Neutral | 0.771 | Possibly Damaging | 0.275 | Benign | 3.39 | Benign | 0.08 | Tolerated | 3.47 | 10 | 1 | 1 | -2.7 | 27.03 | 233.2 | -29.1 | -0.1 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. However, in the variant simulations, the carboxamide side chain of Asn704 achieves more lasting and numerous hydrogen-bonding interactions with the residues at the helix end, such as Glu706, Ala707, and Leu708. Consequently, the residue swap could strengthen the α-helix secondary structure integrity at the helix end, which could have either positive or negative effects on its function. | ||||||||
| c.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.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.3377G>A | G1126D 2D AISynGAP1 missense variant G1126D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The AlphaMissense‑Default result is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -8.888 | Likely Pathogenic | 0.432 | Ambiguous | Likely Benign | 0.376 | Likely Benign | -0.65 | Neutral | 0.906 | Possibly Damaging | 0.473 | Possibly Damaging | 4.82 | Benign | 0.02 | Affected | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||
| c.2195G>C | R732T 2D  AISynGAP1 missense variant R732T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b). AlphaMissense‑Default remains uncertain. The high‑accuracy AlphaMissense‑Optimized predicts a benign effect, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors a benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact, which does not contradict the current ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | -8.545 | Likely Pathogenic | 0.434 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.892 | Possibly Damaging | 2.59 | Benign | 0.12 | Tolerated | 3.59 | 7 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||
| c.59C>G | P20R 2D AIThe SynGAP1 missense variant P20R is listed in ClinVar (ID 566521.0) 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools 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 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 current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.548 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -0.15 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| 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.2113A>C | K705Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K705Q missense variant (ClinVar ID 3699560.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (variant ID 6‑33441372‑A‑C). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (benign)—also yields a benign classification; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence supports a benign impact for K705Q, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33441372-A-C | 1 | 6.20e-7 | -5.787 | Likely Benign | 0.436 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -0.10 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.12 | Likely Benign | -0.02 | Likely Benign | -0.24 | Neutral | 0.997 | Probably Damaging | 0.969 | Probably Damaging | 3.42 | Benign | 0.78 | Tolerated | 3.47 | 10 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||
| c.1147G>T | G383W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G383W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438052‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta as pathogenic. Because the majority of conventional predictors favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic interpretation. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438052-G-T | 1 | 6.22e-7 | -10.161 | Likely Pathogenic | 0.439 | Ambiguous | Likely Benign | 0.469 | Likely Benign | 5.81 | Destabilizing | 3.6 | 4.44 | Destabilizing | 5.13 | Destabilizing | 0.08 | Likely Benign | -1.01 | Neutral | 0.959 | Probably Damaging | 0.704 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 4.32 | 7 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||
| c.3820C>T | R1274C 2D AIThe SynGAP1 missense variant R1274C is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (ID 6‑33447868‑C‑T). Prediction tools that agree on benign impact include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). AlphaMissense‑Default remains uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and no Foldetta data to weigh in. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) suggest a pathogenic effect. This consensus does not contradict the ClinVar “Uncertain” status, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33447868-C-T | -6.467 | Likely Benign | 0.439 | Ambiguous | Likely Benign | 0.170 | Likely Benign | -5.22 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||||
| c.1973G>A | G658D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G658D is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33441232‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome, while Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta, which integrates FoldX‑MD and Rosetta, is also inconclusive. Overall, the preponderance of evidence points to a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33441232-G-A | 3 | 1.86e-6 | -7.786 | In-Between | 0.442 | Ambiguous | Likely Benign | 0.144 | Likely Benign | -0.40 | Likely Benign | 0.1 | -0.59 | Ambiguous | -0.50 | Ambiguous | 0.46 | Likely Benign | -2.64 | Deleterious | 0.008 | Benign | 0.005 | Benign | 3.53 | Benign | 0.38 | Tolerated | 3.39 | 24 | 1 | -1 | -3.1 | 58.04 | 219.8 | -84.3 | 0.0 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Gly658, located on the outer surface of an α helix (res. Ser641-Glu666), weakens the helix integrity at that spot, which is necessary for the kink in the middle of the long helix. In the variant simulations, the carboxylic acid side chain of Asp658 is on the surface of the α helix and is not involved in any interactions. However, aspartate is not as effective a breaker of the secondary structure element as glycine, which may lead to misfolding. | |||||||||
| c.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.3824G>T | R1275L 2D AIThe SynGAP1 missense variant R1275L is listed in ClinVar as benign and is present in gnomAD (ID 6‑33447872‑G‑T). Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar, while pathogenic calls come from PROVEAN, polyPhen2_HumDiv, and SIFT. Grouping by agreement, the benign‑predicted tools outnumber the pathogenic ones (5 vs 3). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the computational evidence leans toward a benign effect, consistent with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 1 | 6-33447872-G-T | 1 | 6.45e-7 | -6.052 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -4.04 | Deleterious | 0.800 | Possibly Damaging | 0.277 | Benign | 2.55 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||
| c.3413C>A | S1138Y 2D AIThe SynGAP1 missense variant S1138Y is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (ID 6‑33444448‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM Consensus both indicate a benign outcome, while Foldetta data are missing. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This benign prediction does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33444448-C-A | 3 | 1.86e-6 | -6.610 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.41 | Benign | 0.05 | Affected | 4.32 | 4 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||
| 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.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.2302G>A | D768N 2D AIThe SynGAP1 missense variant D768N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442460‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33442460-G-A | 2 | 2.57e-6 | -6.892 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.048 | Likely Benign | -0.77 | Neutral | 0.106 | Benign | 0.009 | Benign | 4.07 | Benign | 0.96 | Tolerated | 3.64 | 6 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||
| c.2434C>T | P812S 2D AIThe SynGAP1 missense variant P812S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442986‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and no Foldetta stability result is available. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | Uncertain | 1 | 6-33442986-C-T | 1 | 6.20e-7 | -5.689 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -0.62 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.89 | Benign | 0.95 | Tolerated | 4.32 | 4 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||
| 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.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.3567G>C | E1189D 2D AIThe SynGAP1 missense variant E1189D (gnomAD ID 6-33444602‑G‑C) is listed in ClinVar as Benign (ClinVar ID 833989.0). In silico predictors that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Predictors that indicate a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as benign, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also favors a benign outcome. No Foldetta stability assessment is available for this residue. Overall, the majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Likely Benign | 1 | 6-33444602-G-C | 3 | 1.86e-6 | -3.582 | Likely Benign | 0.461 | Ambiguous | Likely Benign | 0.359 | Likely Benign | -1.42 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 5.30 | Benign | 0.25 | Tolerated | 3.82 | 4 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.59C>T | P20L 2D AIThe SynGAP1 missense variant P20L (ClinVar ID 1185912.0) 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, 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 status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 3 | -3.289 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.100 | Likely Benign | -0.44 | Neutral | 0.909 | Possibly Damaging | 0.713 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.515G>A | R172Q 2D AISynGAP1 missense variant R172Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435157‑G‑A). Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv and SIFT, while ESM1b and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33435157-G-A | 3 | 1.86e-6 | -7.245 | In-Between | 0.465 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -1.72 | Neutral | 0.804 | Possibly Damaging | 0.091 | Benign | 4.04 | Benign | 0.04 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
| c.3983G>C | R1328P 2D AIThe SynGAP1 missense variant R1328P (ClinVar ID 1258976.0) is classified as Benign in ClinVar and is observed in gnomAD (6‑33451857‑G‑C). 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 and the SGM‑Consensus also indicates a likely benign outcome; no Foldetta stability data are reported. 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 | 6-33451857-G-C | -1.220 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.060 | Likely Benign | -2.01 | Neutral | 0.927 | Possibly Damaging | 0.452 | Possibly Damaging | 4.06 | Benign | 0.01 | Affected | 3.77 | 5 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| 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.3355G>A | G1119R 2D AIThe SynGAP1 missense variant G1119R is listed in ClinVar as benign and is present in gnomAD (ID 6‑33443907‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification; there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Benign | 1 | 6-33443907-G-A | 64 | 4.23e-5 | -8.489 | Likely Pathogenic | 0.473 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.10 | Neutral | 0.969 | Probably Damaging | 0.462 | Possibly Damaging | 4.03 | Benign | 0.10 | Tolerated | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| 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.1408A>G | M470V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from most in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all score it as deleterious. Only two tools—SIFT and AlphaMissense‑Optimized—classify it as benign, while Rosetta and AlphaMissense‑Default remain inconclusive. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports a benign outcome, but the SGM‑Consensus (derived from a majority of pathogenic calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining pathogenic FoldX with uncertain Rosetta) both predict pathogenicity. Overall, the preponderance of evidence supports a likely pathogenic classification, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.856 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.770 | Likely Pathogenic | 2.73 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.31 | Destabilizing | 1.31 | Destabilizing | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.20 | Pathogenic | 0.15 | Tolerated | 3.37 | 34 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||
| c.1651C>A | L551M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551M is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438894‑C‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools report an uncertain outcome: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438894-C-A | 7 | 4.34e-6 | -9.937 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.544 | Likely Pathogenic | -0.07 | Likely Benign | 0.1 | 0.13 | Likely Benign | 0.03 | Likely Benign | 0.71 | Ambiguous | -0.56 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 4 | 2 | -1.9 | 18.03 | 246.5 | -18.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the thioether side chain of Met551 can maintain similar hydrophobic interactions as Leu551 in the WT, thus causing no negative effect on the protein structure during the simulations. | |||||||||
| c.2818G>C | G940R 2D AIThe SynGAP1 missense variant G940R is listed in ClinVar (ID 1923639.0) as Benign and is present in gnomAD (6‑33443370‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta data is unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Benign | 1 | 6-33443370-G-C | 5 | 3.10e-6 | -6.169 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.060 | Likely Benign | 0.02 | Neutral | 0.922 | Possibly Damaging | 0.543 | Possibly Damaging | 2.73 | Benign | 0.15 | Tolerated | 3.77 | 5 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.485G>A | R162H 2D AIThe SynGAP1 missense variant R162H is listed in ClinVar with an uncertain significance and is present in the gnomAD database (variant ID 6‑33432782‑G‑A). Functional prediction tools cluster into two groups: benign calls are made by REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 (HumDiv and HumVar) and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant. 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. | Uncertain | 1 | 6-33432782-G-A | 2 | 1.24e-6 | -9.730 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.167 | Likely Benign | -1.13 | Neutral | 0.957 | Probably Damaging | 0.513 | Possibly Damaging | 4.03 | Benign | 0.12 | Tolerated | 3.74 | 4 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
| c.2095G>A | V699M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V699M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441354‑G‑A). Across in silico predictors, benign calls are made by REVEL, Rosetta, Foldetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Default) are noted but not used as evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports benign stability. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the ClinVar uncertain status but provides a stronger leaning toward benignity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 2 | 6-33441354-G-A | 8 | 4.96e-6 | -8.869 | Likely Pathogenic | 0.484 | Ambiguous | Likely Benign | 0.276 | Likely Benign | -0.58 | Ambiguous | 0.1 | 0.29 | Likely Benign | -0.15 | Likely Benign | 0.96 | Ambiguous | -2.18 | Neutral | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.37 | Benign | 0.03 | Affected | 3.47 | 10 | 2 | 1 | -2.3 | 32.06 | 257.8 | -47.2 | 0.0 | 0.0 | 0.9 | 0.1 | X | Potentially Benign | The isopropyl side chain of Val699, located on an α-helix (res. Leu685-Gln702), packs against hydrophobic residues (e.g., Leu703, Leu696, Leu435, Leu439) in the inter-helix space. In the variant simulations, the thioether side chain of Met699 has similar physicochemical properties to Val699 in the WT, and thus, it is able to maintain similar interactions. Consequently, the mutation causes no apparent changes in the structure. | |||||||||
| c.3313C>T | R1105W 2D AIThe SynGAP1 missense variant R1105W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443865‑C‑T). Prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default tool remains uncertain. A consensus analysis (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1105W, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33443865-C-T | 6 | 3.93e-6 | -6.911 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||
| c.2627C>T | S876L 2D AISynGAP1 variant S876L is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive and therefore unavailable; Foldetta stability analysis is also unavailable. Overall, the majority of available predictions favor a benign impact, suggesting the variant is most likely benign. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 2 | -5.856 | Likely Benign | 0.489 | Ambiguous | Likely Benign | 0.249 | Likely Benign | -3.56 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.57 | Benign | 0.05 | Affected | 3.77 | 5 | -2 | -3 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||
| 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.1724G>A | R575H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R575H (ClinVar ID 1029088.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33440776‑G‑A). Prediction tools that indicate a benign effect include Rosetta, Foldetta, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, Foldetta as Benign, and the SGM Consensus as Pathogenic. Overall, the majority of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 4 | 6-33440776-G-A | 204 | 1.27e-4 | -11.142 | Likely Pathogenic | 0.496 | Ambiguous | Likely Benign | 0.707 | Likely Pathogenic | 0.81 | Ambiguous | 0.2 | -0.22 | Likely Benign | 0.30 | Likely Benign | 1.31 | Destabilizing | -2.34 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 244.7 | 80.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Pathogenic | The guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the imidazole ring of His575 (in its neutral epsilon protonated form) cannot form the same salt bridges as the guanidinium group of the non-mutated Arg575. Instead, His575 only forms weak hydrogen bonds with the hydroxyl groups of Ser466 and Ser571. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | |||||||||
| 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.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.1285C>T | R429W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438190‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 5 | 6-33438190-C-T | 65 | 4.03e-5 | -10.666 | Likely Pathogenic | 0.500 | Ambiguous | Likely Benign | 0.282 | Likely Benign | 0.31 | Likely Benign | 0.1 | -0.13 | Likely Benign | 0.09 | Likely Benign | 0.52 | Ambiguous | -3.19 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 3.38 | 25 | 2 | -3 | 3.6 | 30.03 | 252.3 | 45.5 | 0.0 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg429, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or a H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, the indole ring of the Trp429 side chain cannot form ionic interactions with the acidic residues. Although it forms a H-bond with Ser471, the bonding is not as strong as that of arginine. The residue swap could affect the tertiary structure assembly during folding; however, no large-scale negative effects were seen during the simulations. | |||||||||
| c.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 | |||||||||||||||||||||||||||
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