Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.2959G>A | D987N 2D  AIThe SynGAP1 D987N missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -5.035 | Likely Benign | 0.698 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.42 | Neutral | 0.943 | Possibly Damaging | 0.755 | Possibly Damaging | 2.41 | Pathogenic | 0.49 | Tolerated | 0.1331 | 0.7427 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3025G>A | E1009K 2D  AIThe SynGAP1 missense variant E1009K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools (five pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -3.419 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.061 | Likely Benign | -1.90 | Neutral | 0.961 | Probably Damaging | 0.630 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 0.2511 | 0.7625 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.3307C>T | R1103C 2D  AISynGAP1 missense variant R1103C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443859‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized reports a benign outcome, while Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443859-C-T | 6 | 3.92e-6 | -2.440 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -3.01 | Deleterious | 0.996 | Probably Damaging | 0.787 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3376 | 0.4121 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.3618A>C | K1206N 2D  AIThe SynGAP1 missense variant K1206N is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions, K1206N is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -11.172 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | -3.06 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.41 | Pathogenic | 0.01 | Affected | 0.3169 | 0.1464 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3618A>T | K1206N 2D AIThe SynGAP1 missense variant K1206N is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions, K1206N is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -11.172 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | -3.06 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.41 | Pathogenic | 0.01 | Affected | 0.3169 | 0.1464 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.1786C>A | R596S 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R596S is not reported in ClinVar and is absent from gnomAD. In silico assessment shows a consensus of pathogenicity: all evaluated tools (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a deleterious effect, while Rosetta remains uncertain. Grouping by agreement, no tool predicts benign; the pathogenic group includes 13 predictions, with Rosetta excluded as inconclusive. High‑accuracy methods further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.017797 | Structured | 0.135423 | Uncertain | 0.918 | 0.134 | 0.000 | -13.921 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.51 | Destabilizing | 0.2 | 1.53 | Ambiguous | 2.52 | Destabilizing | 1.17 | Destabilizing | 0.626 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3129 | 0.2680 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.1787G>C | R596P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R596P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No contradictory evidence is present. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.017797 | Structured | 0.135423 | Uncertain | 0.918 | 0.134 | 0.000 | -13.786 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.80 | Destabilizing | 0.1 | 4.78 | Destabilizing | 5.79 | Destabilizing | 1.15 | Destabilizing | 0.780 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.2335 | 0.3356 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.2419T>G | Y807D 2D  AIThe SynGAP1 missense variant Y807D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, while the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Uncertain calls come from ESM1b and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for Y807D, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -7.598 | In-Between | 0.862 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | -4.40 | Deleterious | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3944 | 0.0704 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| 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 | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | 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 | 0.3101 | 0.1907 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||
| c.2869C>T | H957Y 2D  AIThe SynGAP1 missense variant H957Y is listed in gnomAD (ID 6‑33443421‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports “Likely Benign.” Pathogenic predictions come from polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | 6-33443421-C-T | 1 | 6.20e-7 | -6.631 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -1.00 | Neutral | 0.510 | Possibly Damaging | 0.147 | Benign | 2.42 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.1560 | 0.4906 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||
| c.2870A>C | H957P 2D  AIThe SynGAP1 H957P missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The high‑accuracy consensus (SGM‑Consensus) is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a Likely Benign classification (3 benign vs. 1 pathogenic). AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.347 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.244 | Likely Benign | -0.61 | Neutral | 0.453 | Possibly Damaging | 0.105 | Benign | 2.42 | Pathogenic | 0.13 | Tolerated | 0.2300 | 0.4701 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3050T>G | F1017C 2D  AIThe SynGAP1 missense variant F1017C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -5.769 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.133 | Likely Benign | -3.71 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.2488 | 0.1137 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.3226T>A | L1076M 2D  AIThe SynGAP1 missense variant L1076M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -5.047 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 0.02 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0.0886 | 0.4147 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3228G>C | L1076F 2D  AIThe SynGAP1 missense variant L1076F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -4.606 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.03 | Affected | 0.0759 | 0.3767 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3228G>T | L1076F 2D AIThe SynGAP1 missense variant L1076F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -4.606 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.03 | Affected | 0.0759 | 0.3767 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3265G>A | G1089R 2D  AIThe SynGAP1 missense variant G1089R is catalogued in gnomAD (ID 6‑33443817‑G‑A) but has no ClinVar entry. Functional prediction tools split in a 6‑to‑3 ratio: benign calls come from REVEL, polyPhen‑2 HumVar, and ESM1b, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized yields an Uncertain result, and no Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors lean toward pathogenicity, and this assessment does not conflict with ClinVar status, which is currently unreported. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | 6-33443817-G-A | 1 | 6.35e-7 | -4.757 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.0934 | 0.4415 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3265G>C | G1089R 2D AIThe SynGAP1 missense variant G1089R is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. Grouping by consensus, seven tools predict pathogenicity and three predict benign, giving a net pathogenic signal. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta stability analysis is unavailable. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -4.757 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.0934 | 0.4415 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3313C>T | R1105W 2D  AIThe SynGAP1 missense variant R1105W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443865‑C‑T). Prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default tool remains uncertain. A consensus analysis (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1105W, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 1 | 6-33443865-C-T | 6 | 3.93e-6 | -6.911 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1154 | 0.4117 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3322A>T | S1108C 2D  AIThe SynGAP1 missense variant S1108C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification, and this conclusion does not contradict any ClinVar status because none is available. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -9.189 | Likely Pathogenic | 0.183 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -3.30 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0.0992 | 0.5299 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3643A>C | K1215Q 2D  AIThe SynGAP1 missense variant K1215Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and PROVEAN, whereas the remaining tools—polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic impact for K1215Q, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.503613 | Binding | 0.888 | 0.568 | 0.375 | -9.763 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.099 | Likely Benign | -2.23 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.42 | Pathogenic | 0.02 | Affected | 0.4002 | 0.0856 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3670C>G | L1224V 2D  AIThe SynGAP1 missense variant L1224V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates a benign likelihood. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | -5.796 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.41 | Neutral | 0.248 | Benign | 0.112 | Benign | 2.42 | Pathogenic | 0.18 | Tolerated | 0.1397 | 0.2289 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3671T>G | L1224R 2D  AIThe SynGAP1 missense variant L1224R is listed in ClinVar with no assertion (ClinVar status: None) and is present in the gnomAD database (ID 6‑33446663‑T‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | 6-33446663-T-G | 1 | 6.20e-7 | -7.504 | In-Between | 0.220 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.85 | Neutral | 0.989 | Probably Damaging | 0.900 | Possibly Damaging | 2.42 | Pathogenic | 0.33 | Tolerated | 3.77 | 5 | 0.1120 | 0.0558 | -2 | -3 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||
| c.3780G>C | K1260N 2D AIThe SynGAP1 missense variant K1260N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic or likely pathogenic. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Based on the consensus of high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -9.053 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -3.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3064 | 0.1302 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3780G>T | K1260N 2D AIThe SynGAP1 missense variant K1260N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic or likely pathogenic. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Based on the consensus of high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -9.053 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -3.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3064 | 0.1302 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3857A>T | E1286V 2D  AIThe SynGAP1 missense variant E1286V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑benign/2‑pathogenic split. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.195 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.259 | Likely Benign | -3.90 | Deleterious | 0.960 | Probably Damaging | 0.679 | Possibly Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.0828 | 0.5614 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.1352T>A | L451Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451Q is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -15.426 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 2.48 | Destabilizing | 2.70 | Destabilizing | 2.30 | Destabilizing | 0.708 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0869 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1352T>C | L451P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451P is reported in ClinVar as Pathogenic (ClinVar ID 3064222.0) and is not found in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | Likely Pathogenic | 1 | -14.549 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.92 | Destabilizing | 0.2 | 8.57 | Destabilizing | 7.75 | Destabilizing | 2.58 | Destabilizing | 0.750 | Likely Pathogenic | -6.81 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2823 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1352T>G | L451R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -16.162 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.32 | Destabilizing | 0.1 | 3.76 | Destabilizing | 3.54 | Destabilizing | 2.25 | Destabilizing | 0.726 | Likely Pathogenic | -5.82 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1130 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1416G>C | E472D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472D is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL and SIFT, whereas the majority of tools—SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability estimates. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (derived from the four high‑confidence predictors) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E472D, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -9.798 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.3 | 1.99 | Ambiguous | 1.63 | Ambiguous | 1.00 | Destabilizing | 0.304 | Likely Benign | -2.75 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 0.1975 | 0.3918 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1416G>T | E472D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), FATHMM, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, Foldetta) yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -9.798 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.3 | 1.99 | Ambiguous | 1.63 | Ambiguous | 1.00 | Destabilizing | 0.303 | Likely Benign | -2.75 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 0.1975 | 0.3918 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1787G>A | R596H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R596H is listed in ClinVar as benign (ClinVar ID 1989474.0) and is present in gnomAD (ID 6‑33440839‑G‑A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all report pathogenicity, while only Rosetta predicts a benign outcome. Two tools are inconclusive: AlphaMissense‑Optimized and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the four pathogenic votes) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, directly contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.017797 | Structured | 0.135423 | Uncertain | 0.918 | 0.134 | 0.000 | Likely Benign | 1 | 6-33440839-G-A | 15 | 9.29e-6 | -11.128 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 3.00 | Destabilizing | 0.9 | 0.43 | Likely Benign | 1.72 | Ambiguous | 1.35 | Destabilizing | 0.717 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3290 | 0.1208 | 2 | 0 | 1.3 | -19.05 | 223.5 | 80.5 | -0.1 | 0.0 | -0.1 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the imidazole ring of His596 can form hydrogen bonds with the same residues as arginine; however, these interactions are not as coordinated or strong in comparison. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | ||||||||||||
| c.1879G>C | A627P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A627P is not reported in ClinVar and is absent from gnomAD. Prediction tools were grouped by consensus: Benign – none; Pathogenic – SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. High‑accuracy methods specifically: AlphaMissense‑Optimized predicts pathogenicity; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -15.404 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.78 | Destabilizing | 0.3 | 7.84 | Destabilizing | 6.81 | Destabilizing | 1.13 | Destabilizing | 0.740 | Likely Pathogenic | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.43 | Pathogenic | 0.01 | Affected | 0.1752 | 0.3422 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1880C>A | A627D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627D is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. All available evidence points to a damaging impact. Consequently, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -16.603 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.09 | Destabilizing | 1.3 | 5.83 | Destabilizing | 5.96 | Destabilizing | 1.58 | Destabilizing | 0.726 | Likely Pathogenic | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.961 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1502 | 0.1816 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.2419T>A | Y807N 2D  AIThe SynGAP1 missense variant Y807N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. ESM1b is uncertain. High‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, a protein‑folding stability approach that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -7.795 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.154 | Likely Benign | -4.01 | Deleterious | 0.934 | Possibly Damaging | 0.773 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.2274 | 0.0704 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.2449T>A | S817T 2D  AIThe SynGAP1 missense variant S817T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign, and Foldetta results are unavailable. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign impact for S817T. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.544 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.95 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1622 | 0.6482 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2501T>A | M834K 2D  AIThe SynGAP1 missense variant M834K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.154 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.154 | Likely Benign | -2.21 | Neutral | 0.369 | Benign | 0.150 | Benign | 2.43 | Pathogenic | 0.00 | Affected | 0.1131 | 0.0688 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2501T>G | M834R 2D  AIThe SynGAP1 missense variant M834R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward benign (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for M834R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -2.621 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.148 | Likely Benign | -2.44 | Neutral | 0.812 | Possibly Damaging | 0.284 | Benign | 2.43 | Pathogenic | 0.00 | Affected | 0.1310 | 0.0837 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2693C>G | S898C 2D AIThe SynGAP1 missense variant S898C is catalogued in gnomAD (ID 6‑33443245‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while ESM1b remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus also indicates benign. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, did not return a result for this variant, so its stability impact is unavailable. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with ClinVar, which currently has no classification for S898C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | 6-33443245-C-G | 1 | 6.20e-7 | -7.007 | In-Between | 0.257 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.43 | Neutral | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 2.43 | Pathogenic | 0.01 | Affected | 4.32 | 4 | 0.1487 | 0.6166 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2708G>C | G903A 2D  AIThe SynGAP1 missense variant G903A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G903A. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -2.843 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.54 | Neutral | 0.989 | Probably Damaging | 0.829 | Possibly Damaging | 2.43 | Pathogenic | 0.08 | Tolerated | 0.3490 | 0.5025 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2798A>G | H933R 2D  AIThe SynGAP1 missense variant H933R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -4.410 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.393 | Likely Benign | -3.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 0.2074 | 0.2922 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.2824C>T | P942S 2D  AIThe SynGAP1 missense variant P942S is catalogued in gnomAD (ID 6‑33443376‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | 6-33443376-C-T | 1 | 6.20e-7 | -3.919 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.80 | Neutral | 0.011 | Benign | 0.015 | Benign | 2.43 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 0.3226 | 0.4806 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3046G>T | D1016Y 2D  AIThe SynGAP1 missense variant D1016Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. High‑accuracy assessment therefore points to a Likely Pathogenic classification from SGM‑Consensus, with AlphaMissense‑Optimized inconclusive and Foldetta missing. Based on the preponderance of pathogenic predictions and the lack of contradictory evidence from ClinVar, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -4.432 | Likely Benign | 0.832 | Likely Pathogenic | Ambiguous | 0.350 | Likely Benign | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.947 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1111 | 0.6531 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3055C>A | R1019S 2D AIThe SynGAP1 missense variant R1019S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for R1019S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -3.818 | Likely Benign | 0.871 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | -2.59 | Deleterious | 0.800 | Possibly Damaging | 0.410 | Benign | 2.43 | Pathogenic | 0.01 | Affected | 0.2441 | 0.3979 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3067T>C | S1023P 2D  AIThe SynGAP1 missense variant S1023P is reported in gnomAD (ID 6‑33443619‑T‑C) but has no ClinVar entry (ClinVar status: not reported). Functional prediction tools are split: benign calls come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of standard predictors lean toward pathogenicity, whereas the few high‑accuracy tools do not support a pathogenic verdict. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | 6-33443619-T-C | 2 | 1.24e-6 | -5.634 | Likely Benign | 0.679 | Likely Pathogenic | Likely Benign | 0.146 | Likely Benign | -2.11 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.43 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1818 | 0.4616 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3071T>C | L1024P 2D AIThe SynGAP1 missense variant L1024P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard prediction tools lean toward pathogenicity, while high‑accuracy methods are inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.385 | Likely Benign | 0.730 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.974 | Probably Damaging | 2.43 | Pathogenic | 0.03 | Affected | 0.3187 | 0.2033 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3227T>C | L1076S 2D  AIThe SynGAP1 missense variant L1076S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes); and Foldetta results are unavailable. Consequently, the evidence is evenly split between benign and pathogenic predictions. The variant is therefore most likely of uncertain significance, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -2.975 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.225 | Likely Benign | 0.55 | Neutral | 0.999 | Probably Damaging | 0.983 | Probably Damaging | 2.43 | Pathogenic | 0.75 | Tolerated | 0.3045 | 0.1178 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3308G>C | R1103P 2D AIThe SynGAP1 missense variant R1103P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -2.149 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -2.48 | Neutral | 0.969 | Probably Damaging | 0.659 | Possibly Damaging | 2.43 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5109 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3596A>T | E1199V 2D AIThe SynGAP1 missense change E1199V is not reported in ClinVar and is absent from gnomAD. Prediction tools that flag the variant as benign include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus likewise reports a likely pathogenic outcome. Foldetta results are not available for this variant. Overall, the preponderance of computational evidence points to a pathogenic effect for E1199V, and this conclusion does not conflict with the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.538167 | Disordered | 0.444533 | Uncertain | 0.878 | 0.598 | 0.250 | -12.285 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.360 | Likely Benign | -5.14 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0715 | 0.4581 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3683A>T | E1228V 2D AIThe SynGAP1 missense variant E1228V is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus score, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further separate the evidence: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus, derived from a consensus of four high‑confidence predictors, flags the variant as pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this change. Overall, the preponderance of pathogenic predictions, including the SGM‑Consensus, outweighs the benign calls. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -8.077 | Likely Pathogenic | 0.440 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -4.55 | Deleterious | 0.980 | Probably Damaging | 0.833 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0470 | 0.4252 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3752A>C | Q1251P 2D  AIThe SynGAP1 missense variant Q1251P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -14.584 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.344 | Likely Benign | -4.45 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.2418 | 0.4408 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| c.1393C>G | L465V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports likely pathogenic; and Foldetta, which combines FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Uncertain | 1 | -9.893 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 2.46 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.56 | Destabilizing | 1.21 | Destabilizing | 0.276 | Likely Benign | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.37 | 34 | 0.1493 | 0.3378 | 2 | 1 | 0.4 | -14.03 | 204.3 | 30.9 | 0.0 | 0.0 | -0.4 | 0.6 | X | Potentially Benign | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations. | ||||||||||||||||
| c.1393C>T | L465F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465F is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas the majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus also pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect for L465F. This conclusion is not contradicted by ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -12.626 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.7 | 0.05 | Likely Benign | 1.58 | Ambiguous | 0.52 | Ambiguous | 0.432 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.0771 | 0.2759 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2360C>A | P787H 2D  AIThe SynGAP1 missense variant P787H has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic” (3 pathogenic votes versus 1 benign). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, but this is contradicted by the benign call from AlphaMissense‑Optimized. Because ClinVar has no reported status, there is no conflict with existing clinical annotations. Thus, the variant is most likely pathogenic based on the prevailing computational evidence, though one high‑accuracy tool suggests a benign effect. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.819 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.308 | Likely Benign | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1790 | 0.4061 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||
| c.2419T>C | Y807H 2D  AIThe SynGAP1 missense variant Y807H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic. AlphaMissense‑Optimized remains benign, while Foldetta results are unavailable. Overall, the majority of high‑accuracy and consensus predictors (five out of six) suggest a pathogenic impact, whereas only three predict benign. Consequently, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -5.879 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -2.74 | Deleterious | 0.989 | Probably Damaging | 0.913 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.2530 | 0.0704 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2420A>C | Y807S 2D  AIThe SynGAP1 Y807S variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while those that predict pathogenicity are PROVEAN, SIFT, and FATHMM. AlphaMissense‑Default is uncertain, whereas AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional tools (four benign vs. three pathogenic) suggest a benign effect, and the high‑accuracy AlphaMissense‑Optimized also predicts benign, while the SGM Consensus predicts pathogenic. Based on the balance of evidence, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -5.517 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.093 | Likely Benign | -3.90 | Deleterious | 0.136 | Benign | 0.067 | Benign | 2.44 | Pathogenic | 0.01 | Affected | 0.4561 | 0.1884 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2428C>A | R810S 2D AIThe SynGAP1 R810S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic predictions suggests that R810S is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -5.996 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.204 | Likely Benign | -3.20 | Deleterious | 0.996 | Probably Damaging | 0.900 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.3152 | 0.4556 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2516A>C | K839T 2D  AIThe SynGAP1 missense variant K839T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls are limited to REVEL, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the consensus of the majority of in silico tools indicates that K839T is most likely pathogenic, and this conclusion does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -11.946 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.235 | Likely Benign | -3.79 | Deleterious | 0.986 | Probably Damaging | 0.922 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.2119 | 0.4164 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2517G>C | K839N 2D AIThe SynGAP1 missense variant K839N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in silico tools indicates that K839N is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -10.939 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | -2.94 | Deleterious | 0.996 | Probably Damaging | 0.951 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.3629 | 0.1876 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2517G>T | K839N 2D AIThe SynGAP1 missense variant K839N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that K839N is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -10.939 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | -2.94 | Deleterious | 0.996 | Probably Damaging | 0.951 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.3629 | 0.1876 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2642T>G | L881W 2D  AIThe SynGAP1 missense variant L881W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -6.646 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.014 | Benign | 0.008 | Benign | 2.44 | Pathogenic | 0.00 | Affected | 0.0662 | 0.3288 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.2686G>C | G896R 2D AIThe SynGAP1 missense variant G896R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Consequently, the evidence is evenly split between benign and pathogenic predictions, with no decisive support from the high‑accuracy or folding‑stability analyses. The variant is therefore most likely of uncertain significance; it does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -4.511 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.218 | Likely Benign | -2.45 | Neutral | 0.999 | Probably Damaging | 0.967 | Probably Damaging | 2.44 | Pathogenic | 0.14 | Tolerated | 0.0931 | 0.4228 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2687G>A | G896D 2D  AIThe SynGAP1 missense variant G896D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Consequently, the evidence is evenly split between benign and pathogenic predictions, with no decisive support from the most reliable methods. The variant is therefore classified as of uncertain significance; it does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -4.500 | Likely Benign | 0.905 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.39 | Neutral | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.44 | Pathogenic | 0.16 | Tolerated | 0.1707 | 0.1842 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2693C>A | S898Y 2D  AISynGAP1 missense variant S898Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools and the consensus prediction indicate a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -5.927 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | -2.69 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1244 | 0.6838 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2693C>T | S898F 2D  AIThe SynGAP1 missense variant S898F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -5.242 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.181 | Likely Benign | -2.87 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1183 | 0.6643 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2708G>T | G903V 2D  AIThe SynGAP1 missense variant G903V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the balance of evidence (five benign predictions versus three pathogenic predictions, with no conflicting ClinVar annotation) indicates that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant is not currently catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -4.750 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -1.93 | Neutral | 0.997 | Probably Damaging | 0.959 | Probably Damaging | 2.44 | Pathogenic | 0.95 | Tolerated | 0.1269 | 0.4266 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2755C>G | Q919E 2D  AIThe SynGAP1 missense variant Q919E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 high‑confidence predictions and the consensus score favor a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.352 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -1.13 | Neutral | 0.771 | Possibly Damaging | 0.492 | Possibly Damaging | 2.44 | Pathogenic | 0.05 | Affected | 0.1366 | 0.2692 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2870A>T | H957L 2D  AIThe SynGAP1 missense variant H957L is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains eight tools, whereas the pathogenic group contains only FATHMM. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign result. Foldetta, a protein‑folding stability method, has no available output for this variant. Overall, the preponderance of evidence indicates that H957L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.598 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.38 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.44 | Pathogenic | 0.09 | Tolerated | 0.1525 | 0.5516 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3058C>T | R1020W 2D AIThe SynGAP1 missense variant R1020W is catalogued in gnomAD (ID 6‑33443610‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available. Taken together, the preponderance of evidence indicates that R1020W is most likely pathogenic, and this conclusion does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | 6-33443610-C-T | 6 | 3.72e-6 | -9.378 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -4.14 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1420 | 0.4373 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3100C>A | P1034T 2D  AIThe SynGAP1 missense variant P1034T is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict a pathogenic outcome: SIFT and FATHMM. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions support a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.367 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -2.00 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0.1518 | 0.6620 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3100C>T | P1034S 2D AIThe SynGAP1 missense variant P1034S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for P1034S, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -3.730 | Likely Benign | 0.262 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -2.28 | Neutral | 0.011 | Benign | 0.015 | Benign | 2.44 | Pathogenic | 0.05 | Affected | 0.3044 | 0.5853 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3307C>G | R1103G 2D  AIThe SynGAP1 missense variant R1103G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence—five benign predictions versus four pathogenic, with a benign high‑accuracy tool and no conflicting ClinVar annotation—suggests that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -3.516 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -2.65 | Deleterious | 0.911 | Possibly Damaging | 0.308 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0.3429 | 0.4077 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3308G>T | R1103L 2D  AIThe SynGAP1 missense variant R1103L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443860‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome (3 benign vs. 1 pathogenic votes). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443860-G-T | -2.330 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.35 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2098 | 0.5181 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.3314G>C | R1105P 2D AIThe SynGAP1 missense variant R1105P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of predictions (six benign vs. two pathogenic) suggest a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | -3.325 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -3.22 | Deleterious | 0.007 | Benign | 0.006 | Benign | 2.44 | Pathogenic | 0.08 | Tolerated | 0.2031 | 0.5101 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3323G>T | S1108I 2D  AIThe SynGAP1 missense variant S1108I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443875‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no reported result for this variant. Overall, the balance of evidence (five benign versus four pathogenic predictions) suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | Uncertain | 1 | 6-33443875-G-T | -3.666 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -3.73 | Deleterious | 0.971 | Probably Damaging | 0.604 | Possibly Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.0949 | 0.4602 | -2 | -1 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3616A>G | K1206E 2D  AIThe SynGAP1 missense variant K1206E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and PROVEAN, whereas the majority of tools predict a pathogenic impact: polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for K1206E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -11.025 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.156 | Likely Benign | -1.87 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.44 | Pathogenic | 0.02 | Affected | 0.3247 | 0.1039 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3683A>G | E1228G 2D  AIThe SynGAP1 E1228G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show one benign call (AlphaMissense‑Optimized) and no decisive pathogenic evidence. Overall, the majority of standard tools (5 pathogenic vs 4 benign) indicate a pathogenic likelihood, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -6.273 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.249 | Likely Benign | -4.54 | Deleterious | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.2598 | 0.4030 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3753G>C | Q1251H 2D  AIThe SynGAP1 missense variant Q1251H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while REVEL predicts a benign outcome. Two tools return uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a harmful interpretation: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and AlphaMissense‑Optimized remains inconclusive. No Foldetta stability data are available. Overall, the balance of evidence points to a pathogenic effect for Q1251H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -7.561 | In-Between | 0.937 | Likely Pathogenic | Ambiguous | 0.176 | Likely Benign | -3.71 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1132 | 0.2399 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3753G>T | Q1251H 2D AIThe SynGAP1 missense variant Q1251H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while REVEL predicts a benign outcome. Two tools return uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a harmful interpretation: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and AlphaMissense‑Optimized remains inconclusive. No Foldetta stability data are available. Overall, the balance of evidence points to a pathogenic effect for Q1251H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -7.561 | In-Between | 0.937 | Likely Pathogenic | Ambiguous | 0.176 | Likely Benign | -3.71 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1132 | 0.2399 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3839T>G | M1280R 2D AIThe SynGAP1 missense variant M1280R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for M1280R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -2.347 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.272 | Likely Benign | -1.97 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.44 | Pathogenic | 0.00 | Affected | 0.1339 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3884A>G | Q1295R 2D  AIThe SynGAP1 missense variant Q1295R is catalogued in gnomAD (ID 6‑33447932‑A‑G) but has no ClinVar entry. Functional prediction tools show discordant results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta data are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation, though the presence of several benign predictions and the lack of a ClinVar classification mean the variant’s clinical significance remains uncertain. No contradiction exists with ClinVar status, as no ClinVar claim is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447932-A-G | -3.342 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.351 | Likely Benign | -3.30 | Deleterious | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1432 | 0.1348 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||
| c.3889A>T | R1297W 2D AIThe SynGAP1 missense variant R1297W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is consistent with the lack of ClinVar reporting; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -6.039 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.262 | Likely Benign | -4.45 | Deleterious | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1260 | 0.2587 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3925G>A | V1309M 2D  AIThe SynGAP1 missense variant V1309M is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6-33451799-G-A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact for V1309M, and this conclusion does not contradict ClinVar status, which currently has no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | 6-33451799-G-A | 1 | 6.20e-7 | -4.653 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.18 | Neutral | 0.651 | Possibly Damaging | 0.346 | Benign | 2.44 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.0820 | 0.4116 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||
| c.3926T>C | V1309A 2D  AIThe SynGAP1 missense variant V1309A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.336 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.269 | Likely Benign | -1.31 | Neutral | 0.088 | Benign | 0.085 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 0.2641 | 0.1797 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.1787G>T | R596L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R596L missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Foldetta and premPS, whereas the remaining pathogenic‑predicting tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all indicate a deleterious impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (derived from the same four high‑confidence predictors) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for R596L, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.017797 | Structured | 0.135423 | Uncertain | 0.918 | 0.134 | 0.000 | Uncertain | 1 | -13.197 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.51 | Ambiguous | 0.3 | -0.58 | Ambiguous | 0.47 | Likely Benign | -0.02 | Likely Benign | 0.756 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1755 | 0.3433 | -3 | -2 | 8.3 | -43.03 | 234.2 | 63.4 | -0.1 | 0.0 | -0.5 | 0.6 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).However, in the variant simulations, the branched hydrocarbon side chain of Leu596 cannot form any of the hydrogen bonds or salt bridges maintained by the considerably bulkier and positively charged Arg596 side chain. Instead, Leu596 packs hydrophobically with the phenyl ring of Phe484 in the linker loop or residues from the opposing helix (e.g., Ile494, Thr491).Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.2248G>A | G750R 2D AIThe SynGAP1 missense variant G750R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33441713‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | 6-33441713-G-A | 17 | 1.05e-5 | -3.861 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.09 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.99 | 5 | 0.0960 | 0.4015 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2248G>C | G750R 2D AIThe SynGAP1 missense variant G750R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of standard predictors (5 pathogenic vs 4 benign) lean toward pathogenicity, and no ClinVar annotation contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.861 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.09 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.99 | 5 | 0.0960 | 0.4015 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2249G>T | G750V 2D AIThe SynGAP1 missense variant G750V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show AlphaMissense‑Optimized as benign, while the remaining high‑confidence tools (PROVEAN, polyPhen‑2, SIFT, FATHMM) all indicate pathogenicity. Overall, the majority of evidence (five pathogenic vs four benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -4.512 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.54 | Deleterious | 0.984 | Probably Damaging | 0.850 | Possibly Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.1270 | 0.4212 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2261A>T | E754V 2D AIThe SynGAP1 missense variant E754V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions) and the high‑accuracy benign call suggest that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -6.147 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.157 | Likely Benign | -1.86 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.45 | Pathogenic | 0.28 | Tolerated | 0.0730 | 0.7417 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2360C>T | P787L 2D  AIThe SynGAP1 missense variant P787L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) lean toward pathogenicity, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -3.924 | Likely Benign | 0.747 | Likely Pathogenic | Likely Benign | 0.256 | Likely Benign | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.2254 | 0.6034 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2449T>G | S817A 2D  AIThe SynGAP1 missense variant S817A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign, while Foldetta results are unavailable. Overall, the majority of high‑confidence predictions indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.321 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -1.86 | Neutral | 0.977 | Probably Damaging | 0.846 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.5207 | 0.5866 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2501T>C | M834T 2D  AIThe SynGAP1 missense variant M834T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for M834T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.525 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -2.03 | Neutral | 0.224 | Benign | 0.085 | Benign | 2.45 | Pathogenic | 0.00 | Affected | 0.1757 | 0.1799 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2591C>A | A864E 2D  AIThe SynGAP1 missense variant A864E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, which evaluates protein‑folding stability, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | -5.508 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.153 | Likely Benign | 0.10 | Neutral | 0.138 | Benign | 0.070 | Benign | 2.45 | Pathogenic | 0.04 | Affected | 0.1204 | 0.2037 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2591C>T | A864V 2D  AIThe SynGAP1 missense variant A864V is listed in ClinVar with an uncertain significance (ClinVar ID 655662.0) and is observed in gnomAD (ID 6‑33443143‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, which does not contradict its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | Uncertain | 2 | 6-33443143-C-T | 6 | 3.72e-6 | -4.749 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -1.35 | Neutral | 0.767 | Possibly Damaging | 0.119 | Benign | 2.45 | Pathogenic | 0.30 | Tolerated | 3.82 | 4 | 0.1170 | 0.6838 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.2692T>C | S898P 2D AIThe SynGAP1 missense variant S898P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.192 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.44 | Neutral | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.2400 | 0.6555 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2716C>A | L906I 2D  AIThe SynGAP1 missense variant L906I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for this variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -5.882 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.50 | Neutral | 0.905 | Possibly Damaging | 0.545 | Possibly Damaging | 2.45 | Pathogenic | 0.32 | Tolerated | 0.1060 | 0.4093 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2761C>G | L921V 2D AIThe SynGAP1 missense variant L921V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -4.131 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.03 | Neutral | 0.835 | Possibly Damaging | 0.524 | Possibly Damaging | 2.45 | Pathogenic | 0.27 | Tolerated | 0.1483 | 0.3178 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2869C>A | H957N 2D  AIThe SynGAP1 missense variant H957N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.804 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.45 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.45 | Pathogenic | 0.50 | Tolerated | 0.2343 | 0.3788 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2869C>G | H957D 2D  AIThe SynGAP1 missense variant H957D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (7 benign vs 2 pathogenic) supports a benign classification. This prediction is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -8.777 | Likely Pathogenic | 0.237 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -0.77 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.45 | Pathogenic | 0.44 | Tolerated | 0.2646 | 0.3066 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2960A>G | D987G 2D  AIThe SynGAP1 missense variant D987G (ClinVar ID 1061058.0) is listed as ClinVar status Uncertain and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and ESM1b, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further indicate that AlphaMissense‑Optimized is uncertain, while Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, aligning with the SGM‑Consensus but contradicting the ClinVar Uncertain designation. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment is in conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | Uncertain | 1 | -4.782 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.79 | Deleterious | 0.943 | Possibly Damaging | 0.808 | Possibly Damaging | 2.45 | Pathogenic | 0.07 | Tolerated | 4.32 | 2 | 0.3835 | 0.6710 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.3007A>T | S1003C 2D AIThe SynGAP1 missense variant S1003C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is classified as Likely Pathogenic. AlphaMissense‑Optimized, a high‑accuracy tool, predicts a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy consensus, support a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -8.058 | Likely Pathogenic | 0.647 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.98 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.1442 | 0.5966 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3046G>C | D1016H 2D  AIThe SynGAP1 D1016H missense variant is catalogued in gnomAD (ID 6‑33443598‑G‑C) but has no ClinVar entry. Functional prediction tools split in two groups: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized score is uncertain, and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a deleterious effect. Consequently, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | 6-33443598-G-C | -3.398 | Likely Benign | 0.792 | Likely Pathogenic | Ambiguous | 0.259 | Likely Benign | -2.63 | Deleterious | 0.994 | Probably Damaging | 0.924 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2348 | 0.7744 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||
| c.3047A>T | D1016V 2D  AIThe SynGAP1 D1016V missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give an uncertain result from AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no available data from Foldetta. Overall, the majority of evidence points toward a deleterious effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.208 | Likely Benign | 0.800 | Likely Pathogenic | Ambiguous | 0.362 | Likely Benign | -3.80 | Deleterious | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.1424 | 0.7116 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3070C>A | L1024I 2D AIThe SynGAP1 missense variant L1024I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.794 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.99 | Neutral | 0.959 | Probably Damaging | 0.642 | Possibly Damaging | 2.45 | Pathogenic | 0.11 | Tolerated | 0.0992 | 0.3735 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3266G>C | G1089A 2D AIThe SynGAP1 missense variant G1089A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -2.864 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.73 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.45 | Pathogenic | 0.02 | Affected | 0.3475 | 0.5331 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3272T>C | L1091P 2D AIThe SynGAP1 missense variant L1091P is listed in gnomAD (ID 6‑33443824‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, leaving it inconclusive. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of tools (five pathogenic vs three benign) predict a deleterious effect, and the high‑accuracy AlphaMissense‑Optimized score is uncertain. Consequently, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | 6-33443824-T-C | -4.139 | Likely Benign | 0.871 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.45 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3199 | 0.1918 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||
| c.3281C>A | S1094Y 2D AIThe SynGAP1 missense variant S1094Y is not reported in ClinVar (status: none) but is present in gnomAD (ID 6‑33443833‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show a benign call from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the balance of evidence leans toward a pathogenic interpretation (five pathogenic versus four benign calls), and this does not contradict the ClinVar status, which currently has no assertion for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | 6-33443833-C-A | -5.609 | Likely Benign | 0.631 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -2.07 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1007 | 0.5877 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||
| c.3281C>G | S1094C 2D AIThe SynGAP1 missense variant S1094C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools—AlphaMissense‑Default and ESM1b—return uncertain results. High‑accuracy assessments are limited: AlphaMissense‑Optimized indicates a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields no clear consensus and is treated as unavailable; Foldetta data are not provided, so its stability prediction is also unavailable. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -7.143 | In-Between | 0.425 | Ambiguous | Likely Benign | 0.131 | Likely Benign | -1.81 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 2.45 | Pathogenic | 0.05 | Affected | 0.1403 | 0.6309 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3281C>T | S1094F 2D AIThe SynGAP1 missense variant S1094F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -5.655 | Likely Benign | 0.666 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | -2.17 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.0925 | 0.5851 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3313C>G | R1105G 2D AIThe SynGAP1 missense variant R1105G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessment gives a benign prediction from AlphaMissense‑Optimized, a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no result from Foldetta, so its stability impact is unavailable. Overall, the majority of tools lean toward a benign effect, but the high‑accuracy consensus is conflicted. Thus, the variant is most likely benign based on the bulk of predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | -4.900 | Likely Benign | 0.438 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -3.48 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.45 | Pathogenic | 0.09 | Tolerated | 0.3293 | 0.4269 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3506A>G | E1169G 2D AIThe SynGAP1 missense variant E1169G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic classification. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -3.172 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.203 | Likely Benign | -2.33 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.3005 | 0.6019 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3596A>G | E1199G 2D AIThe SynGAP1 missense change E1199G is not reported in ClinVar (ClinVar ID = None) and has no entries in gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E1199G, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.538167 | Disordered | 0.444533 | Uncertain | 0.878 | 0.598 | 0.250 | -13.414 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.360 | Likely Benign | -5.08 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.2461 | 0.3960 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.3640C>T | R1214W 2D AIThe SynGAP1 missense variant R1214W is listed in ClinVar with an uncertain significance (ClinVar ID 1476244.0) and is present in the gnomAD database (gnomAD ID 6‑33446632‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | Uncertain | 1 | 6-33446632-C-T | 2 | 1.24e-6 | -8.799 | Likely Pathogenic | 0.710 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | -4.95 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1186 | 0.2367 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||
| c.3857A>G | E1286G 2D AIThe SynGAP1 missense variant E1286G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence (five benign vs four pathogenic predictions) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has not been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.763 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -3.36 | Deleterious | 0.770 | Possibly Damaging | 0.327 | Benign | 2.45 | Pathogenic | 0.01 | Affected | 0.2904 | 0.4942 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3890G>T | R1297M 2D  AIThe SynGAP1 missense variant R1297M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -4.286 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -3.00 | Deleterious | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.1294 | 0.2449 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.1882A>C | K628Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta, all of which score the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The premPS tool yields an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | -12.263 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.0 | -0.16 | Likely Benign | 0.15 | Likely Benign | 0.95 | Ambiguous | 0.587 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.3444 | 0.1358 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.2160C>A | D720E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D720E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -5.527 | Likely Benign | 0.391 | Ambiguous | Likely Benign | -0.31 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.36 | Likely Benign | 0.23 | Likely Benign | 0.131 | Likely Benign | -2.46 | Neutral | 0.975 | Probably Damaging | 0.969 | Probably Damaging | 2.46 | Pathogenic | 0.15 | Tolerated | 0.1310 | 0.5275 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.2160C>G | D720E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -5.527 | Likely Benign | 0.391 | Ambiguous | Likely Benign | -0.31 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.36 | Likely Benign | 0.23 | Likely Benign | 0.131 | Likely Benign | -2.46 | Neutral | 0.975 | Probably Damaging | 0.969 | Probably Damaging | 2.46 | Pathogenic | 0.15 | Tolerated | 0.1310 | 0.5275 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.2164A>T | S722C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the majority of individual predictors and the high‑accuracy methods lean toward a benign impact, with only the SGM Consensus suggesting pathogenicity. Thus, the variant is most likely benign based on the available predictions, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -8.060 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.0 | -0.23 | Likely Benign | -0.01 | Likely Benign | 0.28 | Likely Benign | 0.362 | Likely Benign | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 2.46 | Pathogenic | 0.05 | Affected | 0.1132 | 0.4306 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.2359C>A | P787T 2D AISynGAP1 missense variant P787T is listed in ClinVar as benign (ClinVar ID 862728.0) and is present in gnomAD (6‑33442911‑C‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by AlphaMissense‑Default, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized result is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, which contradicts the ClinVar benign classification. Thus, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | Likely Benign | 1 | 6-33442911-C-A | 17 | 1.05e-5 | -4.813 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.258 | Likely Benign | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.46 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.1577 | 0.5629 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||
| c.2687G>T | G896V 2D AIThe SynGAP1 missense variant G896V is reported in gnomAD (6-33443239-G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign outcome. Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for G896V, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | 6-33443239-G-T | 1 | 6.20e-7 | -2.936 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.165 | Likely Benign | -1.96 | Neutral | 0.997 | Probably Damaging | 0.912 | Probably Damaging | 2.46 | Pathogenic | 0.30 | Tolerated | 4.32 | 4 | 0.1264 | 0.4026 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.2716C>G | L906V 2D AIThe SynGAP1 missense variant L906V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a damaging or pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a Likely Benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -5.105 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.64 | Neutral | 0.981 | Probably Damaging | 0.832 | Possibly Damaging | 2.46 | Pathogenic | 0.21 | Tolerated | 0.1632 | 0.3744 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2806G>C | A936P 2D AIThe SynGAP1 missense variant A936P is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. No Foldetta stability prediction is available. Overall, the computational evidence overwhelmingly points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.973218 | Binding | 0.319 | 0.874 | 0.625 | -2.782 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.014 | Likely Benign | -1.28 | Neutral | 0.012 | Benign | 0.011 | Benign | 2.46 | Pathogenic | 0.06 | Tolerated | 0.2043 | 0.6109 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3047A>G | D1016G 2D AIThe SynGAP1 missense variant D1016G has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support this split: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -1.918 | Likely Benign | 0.621 | Likely Pathogenic | Likely Benign | 0.209 | Likely Benign | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.652 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 0.3624 | 0.7059 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3050T>C | F1017S 2D  AIThe SynGAP1 missense variant F1017S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -1.804 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -3.16 | Deleterious | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.4491 | 0.0000 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3059G>C | R1020P 2D AIThe SynGAP1 missense variant R1020P is listed in ClinVar (ID 3700393.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Pathogenic” (3 pathogenic vs. 1 benign votes). High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, 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 Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | Uncertain | 1 | -3.491 | Likely Benign | 0.902 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.2077 | 0.5109 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||
| c.3203T>G | L1068W 2D AIThe SynGAP1 missense variant L1068W is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves as pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for L1068W. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -8.574 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -1.96 | Neutral | 0.994 | Probably Damaging | 0.884 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.0742 | 0.3763 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3280T>C | S1094P 2D AIThe SynGAP1 missense variant S1094P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1094P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -2.430 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.31 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.46 | Pathogenic | 0.13 | Tolerated | 0.2322 | 0.6099 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3314G>T | R1105L 2D AIThe SynGAP1 missense variant R1105L is not reported in ClinVar and is present in gnomAD (ID 6‑33443866‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this residue, so its stability impact is unavailable. Overall, the balance of evidence leans toward a benign effect, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | 6-33443866-G-T | -4.031 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -3.51 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.46 | Pathogenic | 0.19 | Tolerated | 3.77 | 5 | 0.1734 | 0.5373 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||
| c.3322A>G | S1108G 2D  AIThe SynGAP1 missense variant S1108G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.496 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -2.59 | Deleterious | 0.568 | Possibly Damaging | 0.239 | Benign | 2.46 | Pathogenic | 0.16 | Tolerated | 0.2268 | 0.3975 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| 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. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | 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 | 0.3232 | 0.1517 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||||
| c.3857A>C | E1286A 2D  AIThe SynGAP1 missense variant E1286A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.136 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -2.37 | Neutral | 0.770 | Possibly Damaging | 0.303 | Benign | 2.46 | Pathogenic | 0.02 | Affected | 0.3820 | 0.5016 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3875T>A | L1292H 2D  AIThe SynGAP1 missense variant L1292H is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33447923‑T‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with a slight tilt toward pathogenicity (five pathogenic vs. four benign). Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | 6-33447923-T-A | -5.692 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -4.42 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1271 | 0.0649 | -3 | -2 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||
| c.3875T>C | L1292P 2D AISynGAP1 missense variant L1292P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑to‑2 split and is therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. With half the tools indicating benign and half indicating pathogenic, the overall computational evidence is ambiguous. Consequently, the variant is neither clearly benign nor pathogenic based on current predictions, and there is no ClinVar entry to contradict this uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -3.761 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -4.58 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 0.3855 | 0.1220 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3875T>G | L1292R 2D AIThe SynGAP1 missense variant L1292R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -4.249 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -4.34 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.1286 | 0.0849 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.1583C>A | P528H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence supports a pathogenic interpretation, and this is consistent with the absence of a ClinVar entry; there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -15.365 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 1.93 | Ambiguous | 0.1 | 0.74 | Ambiguous | 1.34 | Ambiguous | 0.61 | Ambiguous | 0.565 | Likely Pathogenic | -8.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.1434 | 0.3523 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.1880C>T | A627V 2D AIThe SynGAP1 missense variant A627V is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign effect. Two tools return uncertain results: Rosetta and premPS. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -12.150 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 2.64 | Destabilizing | 1.5 | 1.59 | Ambiguous | 2.12 | Destabilizing | 0.74 | Ambiguous | 0.549 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.900 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.0856 | 0.4551 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.2216A>T | E739V 2D AIThe SynGAP1 missense variant E739V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | Uncertain | 1 | -3.136 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.86 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | 4.32 | 2 | 0.0953 | 0.7431 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.2476G>T | D826Y 2D AIThe SynGAP1 missense variant D826Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL classifies it as benign, whereas the remaining predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label it pathogenic. The consensus score from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus also indicates Likely Pathogenic; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a pathogenic effect for D826Y. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -8.029 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | -4.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.0683 | 0.7410 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2515A>C | K839Q 2D AIThe SynGAP1 missense variant K839Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions and the consensus call indicate a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -10.631 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -1.98 | Neutral | 0.972 | Probably Damaging | 0.862 | Possibly Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.4544 | 0.1437 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2515A>G | K839E 2D AIThe SynGAP1 missense variant K839E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic predictions versus four benign, plus a Likely Pathogenic consensus—suggests the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.642678 | Disordered | 0.611185 | Binding | 0.282 | 0.865 | 0.375 | -12.616 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -1.90 | Neutral | 0.316 | Benign | 0.139 | Benign | 2.47 | Pathogenic | 0.01 | Affected | 0.3822 | 0.1198 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2602G>T | D868Y 2D AIThe SynGAP1 missense variant D868Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate deleteriousness. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for D868Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -6.031 | Likely Benign | 0.815 | Likely Pathogenic | Ambiguous | 0.256 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.47 | Pathogenic | 0.05 | Affected | 0.1115 | 0.6847 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2666G>C | G889A 2D AIThe SynGAP1 missense variant G889A is listed in gnomAD (6‑33443218‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome, representing a single dissenting signal. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | 6-33443218-G-C | 1 | 6.20e-7 | -4.580 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.49 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.47 | Pathogenic | 0.76 | Tolerated | 4.32 | 4 | 0.3838 | 0.4902 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2800A>G | M934V 2D  AIThe SynGAP1 missense variant M934V is listed in gnomAD (ID 6‑33443352‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome, representing a single dissenting signal. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that M934V is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | 6-33443352-A-G | 1 | 6.20e-7 | -3.286 | Likely Benign | 0.218 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -2.06 | Neutral | 0.166 | Benign | 0.101 | Benign | 2.47 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | 0.3464 | 0.3276 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.3050T>A | F1017Y 2D  AIThe SynGAP1 missense variant F1017Y is reported in gnomAD (6‑33443602‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | 6-33443602-T-A | -3.583 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.75 | Neutral | 0.012 | Benign | 0.044 | Benign | 2.47 | Pathogenic | 0.05 | Affected | 3.77 | 5 | 0.1432 | 0.1801 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3068C>T | S1023L 2D  AIThe SynGAP1 missense variant S1023L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the balance of evidence from the majority of tools and the SGM‑Consensus indicates a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.735 | Likely Benign | 0.705 | Likely Pathogenic | Likely Benign | 0.204 | Likely Benign | -3.47 | Deleterious | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.47 | Pathogenic | 0.01 | Affected | 0.1080 | 0.4923 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3070C>G | L1024V 2D AIThe SynGAP1 missense variant L1024V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.758 | Likely Benign | 0.244 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.33 | Neutral | 0.907 | Possibly Damaging | 0.642 | Possibly Damaging | 2.47 | Pathogenic | 0.08 | Tolerated | 0.1459 | 0.3185 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3076G>T | D1026Y 2D AIThe SynGAP1 missense variant D1026Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -6.999 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.200 | Likely Benign | -3.08 | Deleterious | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.0676 | 0.4936 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | 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 | 0.3028 | 0.5622 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3272T>A | L1091Q 2D AIThe SynGAP1 missense variant L1091Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -4.381 | Likely Benign | 0.854 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.32 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.1192 | 0.1514 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3272T>G | L1091R 2D AIThe SynGAP1 missense variant L1091R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of consensus tools (five pathogenic vs. three benign) suggest a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -3.662 | Likely Benign | 0.896 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | -1.51 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.02 | Affected | 0.1274 | 0.1357 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3323G>A | S1108N 2D  AIThe SynGAP1 missense variant S1108N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1108N, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.488 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -2.02 | Neutral | 0.611 | Possibly Damaging | 0.239 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 0.1283 | 0.3952 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3622C>T | R1208W 2D AIThe SynGAP1 missense variant R1208W is recorded in gnomAD (variant ID 6‑33446614‑C‑T) but has no ClinVar entry. Prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic.” No Foldetta stability result is available. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that R1208W is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.566942 | Binding | 0.899 | 0.569 | 0.375 | 6-33446614-C-T | 1 | 6.20e-7 | -12.124 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -5.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.47 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1247 | 0.2962 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3641G>C | R1214P 2D AIThe SynGAP1 missense variant R1214P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are not available. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for R1214P. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | -16.520 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.161 | Likely Benign | -4.09 | Deleterious | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.01 | Affected | 0.2055 | 0.3077 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.3683A>C | E1228A 2D AIThe SynGAP1 missense variant E1228A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, the majority of predictions (5 pathogenic vs 4 benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -6.902 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -3.59 | Deleterious | 0.910 | Possibly Damaging | 0.554 | Possibly Damaging | 2.47 | Pathogenic | 0.01 | Affected | 0.2922 | 0.4105 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3856G>A | E1286K 2D AIThe SynGAP1 missense variant E1286K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447904‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs. 3 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet classified there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | 6-33447904-G-A | -3.784 | Likely Benign | 0.395 | Ambiguous | Likely Benign | 0.195 | Likely Benign | -2.36 | Neutral | 0.770 | Possibly Damaging | 0.242 | Benign | 2.47 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2069 | 0.5117 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||
| c.3856G>C | E1286Q 2D  AIThe SynGAP1 missense variant E1286Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.858 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -1.84 | Neutral | 0.872 | Possibly Damaging | 0.478 | Possibly Damaging | 2.47 | Pathogenic | 0.03 | Affected | 0.1185 | 0.4829 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1583C>T | P528L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Because the majority of evidence points to a deleterious effect and no ClinVar annotation exists to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -13.752 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.1 | 0.61 | Ambiguous | 0.96 | Ambiguous | 0.19 | Likely Benign | 0.555 | Likely Pathogenic | -9.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1975 | 0.5574 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.2165G>T | S722I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S722I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, premPS, SIFT, and the folding‑stability method Foldetta, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are provided by AlphaMissense‑Optimized, FoldX, and Rosetta. High‑accuracy analyses further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact on protein stability. Overall, the majority of evidence leans toward a pathogenic interpretation, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -11.165 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.69 | Ambiguous | 0.1 | -0.65 | Ambiguous | 0.02 | Likely Benign | 0.18 | Likely Benign | 0.232 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.48 | Pathogenic | 0.07 | Tolerated | 0.0776 | 0.4187 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.2206C>T | R736C 2D AISynGAP1 missense variant R736C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441671‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign effect, which does not conflict with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | Conflicting | 3 | 6-33441671-C-T | 8 | 4.96e-6 | -7.113 | In-Between | 0.120 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -2.06 | Neutral | 0.999 | Probably Damaging | 0.825 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 4.07 | 3 | 0.3740 | 0.1691 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.2260G>C | E754Q 2D AIThe SynGAP1 missense variant E754Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -5.324 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.76 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.48 | Pathogenic | 0.27 | Tolerated | 0.1112 | 0.6714 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2287C>A | L763I 2D AIThe SynGAP1 missense variant L763I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and there is no conflict with ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -4.803 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.55 | Neutral | 0.877 | Possibly Damaging | 0.675 | Possibly Damaging | 2.48 | Pathogenic | 0.31 | Tolerated | 0.0870 | 0.3367 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2359C>G | P787A 2D AIThe SynGAP1 P787A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM) predict a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic versus three benign predictions, with the SGM Consensus supporting pathogenicity—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -4.542 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -4.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 0.3425 | 0.4444 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2359C>T | P787S 2D AIThe SynGAP1 P787S variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442911‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | Uncertain | 1 | 6-33442911-C-T | 3 | 1.86e-6 | -4.203 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.221 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.3420 | 0.4675 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2465C>T | T822M 2D  AIThe SynGAP1 missense variant T822M is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443017‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | 6-33443017-C-T | 5 | 3.10e-6 | -4.525 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | -2.11 | Neutral | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.48 | Pathogenic | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.6379 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||||||||||
| c.2477A>T | D826V 2D AIThe SynGAP1 missense variant D826V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for D826V, and this conclusion does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.918 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.428 | Likely Benign | -4.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1017 | 0.8023 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2643G>C | L881F 2D AIThe SynGAP1 missense variant L881F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for L881F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -5.759 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.87 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.0711 | 0.3415 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2643G>T | L881F 2D AIThe SynGAP1 missense variant L881F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for L881F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -5.759 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.87 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.0711 | 0.3415 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2807C>A | A936D 2D AIThe SynGAP1 missense variant A936D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.973218 | Binding | 0.319 | 0.874 | 0.625 | -4.162 | Likely Benign | 0.686 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.63 | Neutral | 0.801 | Possibly Damaging | 0.339 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.1778 | 0.1660 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2807C>G | A936G 2D  AIThe SynGAP1 missense variant A936G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.973218 | Binding | 0.319 | 0.874 | 0.625 | -2.720 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.34 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.48 | Pathogenic | 0.12 | Tolerated | 0.2380 | 0.4529 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2807C>T | A936V 2D AIThe SynGAP1 missense variant A936V is reported in gnomAD (ID 6‑33443359‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy consensus, indicate that A936V is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.973218 | Binding | 0.319 | 0.874 | 0.625 | 6-33443359-C-T | 4 | 2.48e-6 | -4.787 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.58 | Neutral | 0.801 | Possibly Damaging | 0.192 | Benign | 2.48 | Pathogenic | 0.19 | Tolerated | 3.77 | 5 | 0.1586 | 0.6921 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2953A>T | S985C 2D AIThe SynGAP1 missense variant S985C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and PROVEAN, whereas the majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the variant as pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that S985C is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -8.918 | Likely Pathogenic | 0.860 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | -2.49 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1531 | 0.5395 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3007A>C | S1003R 2D  AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3007A>G | S1003G 2D AIThe SynGAP1 missense variant S1003G is catalogued in gnomAD (ID 6‑33443559‑A‑G) but has no ClinVar entry. 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 is uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1003G, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | 6-33443559-A-G | 1 | 6.20e-7 | -5.888 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.088 | Likely Benign | -1.72 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2730 | 0.4789 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3008G>A | S1003N 2D AIThe SynGAP1 missense variant S1003N is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy methods do not overturn this trend. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.175 | Likely Benign | 0.889 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.37 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1798 | 0.5029 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3009C>A | S1003R 2D AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3009C>G | S1003R 2D AIThe SynGAP1 missense variant S1003R (ClinVar ID 1798770.0) is listed as Uncertain in ClinVar and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic), and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect, which contrasts with the ClinVar designation of Uncertain. Thus, the variant is most likely pathogenic, contradicting the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | Uncertain | 1 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3029T>G | F1010C 2D AIThe SynGAP1 missense variant F1010C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -4.442 | Likely Benign | 0.755 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -2.31 | Neutral | 1.000 | Probably Damaging | 0.961 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.2646 | 0.1605 | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3052A>T | T1018S 2D  AIThe SynGAP1 missense variant T1018S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.897 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 0.3426 | 0.3404 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3053C>G | T1018S 2D AIThe SynGAP1 missense variant T1018S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.897 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 0.3426 | 0.3404 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3058C>G | R1020G 2D AIThe SynGAP1 missense variant R1020G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | -4.898 | Likely Benign | 0.868 | Likely Pathogenic | Ambiguous | 0.162 | Likely Benign | -4.26 | Deleterious | 0.990 | Probably Damaging | 0.894 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.3394 | 0.3721 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3076G>C | D1026H 2D AIThe SynGAP1 missense variant D1026H is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443628‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | 6-33443628-G-C | 1 | 6.20e-7 | -4.412 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.105 | Likely Benign | -2.03 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1470 | 0.5345 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.3077A>T | D1026V 2D AIThe SynGAP1 missense variant D1026V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools that predict a pathogenic effect are PROVEAN, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore also indicates a likely pathogenic outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available, so it does not contribute evidence. Overall, the majority of reliable predictors classify the variant as pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -5.871 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -3.13 | Deleterious | 0.004 | Benign | 0.004 | Benign | 2.48 | Pathogenic | 0.00 | Affected | 0.0957 | 0.5236 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3148G>A | G1050R 2D AIThe SynGAP1 missense variant G1050R is catalogued in gnomAD (ID 6‑33443700‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | 6-33443700-G-A | 3 | 1.86e-6 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3148G>C | G1050R 2D AIThe SynGAP1 missense variant G1050R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3307C>A | R1103S 2D AIThe SynGAP1 missense variant R1103S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the majority of evidence (six benign versus two pathogenic predictions) indicates that R1103S is most likely benign, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -3.611 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.111 | Likely Benign | -1.94 | Neutral | 0.511 | Possibly Damaging | 0.187 | Benign | 2.48 | Pathogenic | 0.28 | Tolerated | 0.3025 | 0.4224 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3448G>C | A1150P 2D AIThe SynGAP1 missense variant A1150P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (SGM‑Consensus, REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic predictions (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for A1150P, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -2.250 | Likely Benign | 0.180 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.74 | Neutral | 0.995 | Probably Damaging | 0.940 | Probably Damaging | 2.48 | Pathogenic | 0.25 | Tolerated | 0.1896 | 0.5294 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3505G>C | E1169Q 2D AIThe SynGAP1 missense variant E1169Q is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444540‑G‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are made by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and no evidence from ClinVar contradicts this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | 6-33444540-G-C | 1 | 6.20e-7 | -3.096 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -1.27 | Neutral | 0.872 | Possibly Damaging | 0.701 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.88 | 3 | 0.0940 | 0.6392 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3596A>C | E1199A 2D AIThe SynGAP1 missense variant E1199A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. The high‑accuracy consensus, SGM‑Consensus, also indicates a likely pathogenic outcome, while AlphaMissense‑Optimized is uncertain and Foldetta results are unavailable. Taken together, the majority of evidence points to a pathogenic effect for E1199A, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.538167 | Disordered | 0.444533 | Uncertain | 0.878 | 0.598 | 0.250 | -13.556 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.367 | Likely Benign | -4.32 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.2858 | 0.3834 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3640C>G | R1214G 2D AIThe SynGAP1 missense variant R1214G is listed in gnomAD (6‑33446632‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized; those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the majority of tools predict a pathogenic impact, and this conclusion is not contradicted by any ClinVar status (none). Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | 6-33446632-C-G | 1 | 6.20e-7 | -9.697 | Likely Pathogenic | 0.725 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -4.41 | Deleterious | 0.992 | Probably Damaging | 0.828 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3229 | 0.2361 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||
| c.3821G>C | R1274P 2D AIThe SynGAP1 missense variant R1274P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence indicates that R1274P is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | -6.145 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.179 | Likely Benign | -4.02 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.2166 | 0.3095 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3851T>A | L1284Q 2D AIThe SynGAP1 missense variant L1284Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.730 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -2.80 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.1065 | 0.0488 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3851T>C | L1284P 2D AIThe SynGAP1 missense variant L1284P is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (ID 6‑33447899‑T‑C). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. Foldetta results are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation (five pathogenic versus four benign predictions). This assessment does not conflict with ClinVar, as the variant has no ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | 6-33447899-T-C | -2.451 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -3.05 | Deleterious | 0.990 | Probably Damaging | 0.722 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3307 | 0.0848 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||
| c.3851T>G | L1284R 2D AIThe SynGAP1 missense variant L1284R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.203 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -3.11 | Deleterious | 0.990 | Probably Damaging | 0.722 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1216 | 0.0488 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3872T>C | L1291P 2D AIThe SynGAP1 missense variant L1291P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. Because there is no ClinVar assertion, this prediction does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -3.322 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.417 | Likely Benign | -4.32 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.3078 | 0.2162 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1582C>A | P528T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P528T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tools predict a benign outcome. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Uncertain. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -13.782 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 2.05 | Destabilizing | 0.3 | 1.01 | Ambiguous | 1.53 | Ambiguous | 0.66 | Ambiguous | 0.673 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1367 | 0.4360 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1583C>G | P528R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -16.367 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.4 | 0.67 | Ambiguous | 0.72 | Ambiguous | 0.73 | Ambiguous | 0.615 | Likely Pathogenic | -8.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1261 | 0.2543 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1883A>G | K628R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K628R is reported in gnomAD (variant ID 6‑33440935‑A‑G) but has no ClinVar entry. Functional prediction tools show a split assessment: benign calls come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools remain inconclusive (premPS and AlphaMissense‑Default). The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a likely pathogenic verdict, while the high‑accuracy AlphaMissense‑Optimized predicts benign. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the majority of evidence leans toward pathogenicity, and this conclusion does not conflict with ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | 6-33440935-A-G | 1 | 6.20e-7 | -11.324 | Likely Pathogenic | 0.476 | Ambiguous | Likely Benign | 0.22 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.06 | Likely Benign | 0.94 | Ambiguous | 0.592 | Likely Pathogenic | -2.99 | Deleterious | 0.996 | Probably Damaging | 0.990 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.3873 | 0.0873 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||
| c.1901C>A | A634D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634D is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -16.727 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.26 | Destabilizing | 0.5 | 4.24 | Destabilizing | 4.75 | Destabilizing | 1.79 | Destabilizing | 0.731 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1790 | 0.1816 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.2164A>G | S722G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722G is not reported in ClinVar and is present in gnomAD (ID 6‑33441629‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as benign. No evidence from the high‑accuracy tools contradicts the benign predictions, but the consensus and several individual pathogenic predictors suggest a potential deleterious impact. Based on the overall pattern of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and the presence of multiple pathogenic signals. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441629-A-G | 2 | 1.24e-6 | -9.141 | Likely Pathogenic | 0.214 | Likely Benign | Likely Benign | 0.24 | Likely Benign | 0.1 | 0.67 | Ambiguous | 0.46 | Likely Benign | 0.50 | Likely Benign | 0.270 | Likely Benign | -2.72 | Deleterious | 0.998 | Probably Damaging | 0.863 | Possibly Damaging | 2.49 | Pathogenic | 0.14 | Tolerated | 3.50 | 8 | 0.2202 | 0.3400 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||
| c.2216A>G | E739G 2D AIThe SynGAP1 missense variant E739G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of predictions (5 benign vs 4 pathogenic) lean toward a benign impact, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | -3.104 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -2.53 | Deleterious | 0.625 | Possibly Damaging | 0.252 | Benign | 2.49 | Pathogenic | 0.00 | Affected | 0.3335 | 0.5983 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| 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. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | 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 | 0.1326 | 0.3768 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.2261A>C | E754A 2D AIThe SynGAP1 missense variant E754A is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM, while AlphaMissense‑Default remains 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 (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -4.688 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.049 | Likely Benign | -1.56 | Neutral | 0.801 | Possibly Damaging | 0.412 | Benign | 2.49 | Pathogenic | 0.31 | Tolerated | 0.3549 | 0.6283 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2425A>T | S809C 2D AIThe SynGAP1 missense variant S809C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -8.186 | Likely Pathogenic | 0.221 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -1.99 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1088 | 0.6174 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2476G>C | D826H 2D AIThe SynGAP1 missense variant D826H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that D826H is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.437 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.345 | Likely Benign | -3.00 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1757 | 0.8651 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2602G>C | D868H 2D AIThe SynGAP1 missense variant D868H is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (variant ID 6‑33443154‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | 6-33443154-G-C | 1 | 6.20e-7 | -3.358 | Likely Benign | 0.763 | Likely Pathogenic | Likely Benign | 0.212 | Likely Benign | -2.34 | Neutral | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.49 | Pathogenic | 0.08 | Tolerated | 3.82 | 4 | 0.2258 | 0.7837 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.2603A>T | D868V 2D AIThe SynGAP1 missense variant D868V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -5.200 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.182 | Likely Benign | -3.17 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.49 | Pathogenic | 0.25 | Tolerated | 0.1485 | 0.6753 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2641T>A | L881M 2D AIThe SynGAP1 missense variant L881M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -4.419 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.31 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.49 | Pathogenic | 0.03 | Affected | 0.0807 | 0.3997 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2642T>C | L881S 2D AIThe SynGAP1 missense variant L881S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the L881S variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -3.063 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.49 | Neutral | 0.068 | Benign | 0.012 | Benign | 2.49 | Pathogenic | 0.00 | Affected | 0.3363 | 0.0850 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2802G>A | M934I 2D  AIThe SynGAP1 missense variant M934I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus two pathogenic predictions) indicates that M934I is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -4.582 | Likely Benign | 0.757 | Likely Pathogenic | Likely Benign | 0.086 | Likely Benign | -1.78 | Neutral | 0.316 | Benign | 0.101 | Benign | 2.49 | Pathogenic | 0.27 | Tolerated | 0.1686 | 0.3100 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2802G>C | M934I 2D AIThe SynGAP1 missense variant M934I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus two pathogenic predictions) indicates that M934I is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -4.582 | Likely Benign | 0.757 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | -1.78 | Neutral | 0.316 | Benign | 0.101 | Benign | 2.49 | Pathogenic | 0.27 | Tolerated | 0.1686 | 0.3100 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2802G>T | M934I 2D AIThe SynGAP1 missense variant M934I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FATHMM and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus two pathogenic predictions) indicates that M934I is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -4.582 | Likely Benign | 0.757 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | -1.78 | Neutral | 0.316 | Benign | 0.101 | Benign | 2.49 | Pathogenic | 0.27 | Tolerated | 0.1686 | 0.3100 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2824C>A | P942T 2D AIThe SynGAP1 missense variant P942T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for P942T, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -5.745 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.23 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.49 | Pathogenic | 0.00 | Affected | 0.1683 | 0.5599 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3065T>A | L1022H 2D AIThe SynGAP1 missense variant L1022H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (2 pathogenic, 2 benign) and is therefore inconclusive. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.473 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -2.21 | Neutral | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1165 | 0.1313 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3065T>C | L1022P 2D AIThe SynGAP1 missense variant L1022P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). 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, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign), and Foldetta data are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, and this assessment does not conflict with ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.532 | Likely Benign | 0.643 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -2.22 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.3332 | 0.1589 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3067T>A | S1023T 2D AIThe SynGAP1 missense variant S1023T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.573 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.04 | Affected | 0.1299 | 0.5370 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3149G>T | G1050V 2D AIThe SynGAP1 missense variant G1050V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for G1050V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -6.450 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.49 | Pathogenic | 0.13 | Tolerated | 0.1260 | 0.3684 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3202T>A | L1068M 2D AIThe SynGAP1 missense variant L1068M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -5.739 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.22 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.0930 | 0.4582 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3204G>C | L1068F 2D AIThe SynGAP1 missense variant L1068F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) favor a benign classification. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -6.338 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -1.38 | Neutral | 0.934 | Possibly Damaging | 0.537 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.0754 | 0.4202 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3204G>T | L1068F 2D AIThe SynGAP1 missense variant L1068F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) favor a benign classification. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -6.338 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.38 | Neutral | 0.934 | Possibly Damaging | 0.537 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.0754 | 0.4202 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | 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 | 0.2977 | 0.2380 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.3472G>A | V1158I 2D  AIThe SynGAP1 missense variant V1158I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.504 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -0.20 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.49 | Pathogenic | 0.07 | Tolerated | 0.0863 | 0.4180 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3507G>C | E1169D 2D AIThe SynGAP1 missense variant E1169D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools predict a pathogenic impact, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -3.457 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.104 | Likely Benign | -1.12 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1597 | 0.3968 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3507G>T | E1169D 2D AIThe SynGAP1 missense variant E1169D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools predict a pathogenic impact, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -3.457 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -1.12 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1597 | 0.3968 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3617A>G | K1206R 2D AIThe SynGAP1 missense variant K1206R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it receives two benign, one pathogenic, and one uncertain signal. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy AlphaMissense‑Optimized predicts a benign effect, while Foldetta data are missing. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -6.357 | Likely Benign | 0.371 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.64 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.07 | Tolerated | 0.3897 | 0.0945 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3623G>C | R1208P 2D AIThe SynGAP1 missense variant R1208P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for R1208P. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.566942 | Binding | 0.899 | 0.569 | 0.375 | -18.375 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -4.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.2214 | 0.3957 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.3820C>G | R1274G 2D AIThe SynGAP1 R1274G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore predicts a pathogenic outcome. AlphaMissense‑Optimized alone predicts benign, while Foldetta results are unavailable. Overall, the majority of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | -3.288 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | -4.36 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.3316 | 0.2310 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3821G>A | R1274H 2D AIThe SynGAP1 missense variant R1274H (ClinVar ID 2803246.0) is classified as Benign in ClinVar and is present in gnomAD (ID 6‑33447869‑G‑A). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. No Foldetta stability prediction is available for this residue. Overall, the majority of conventional tools predict pathogenicity, and the high‑accuracy AlphaMissense‑Optimized result is benign, leaving the evidence mixed. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, contradicting its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | Likely Benign | 1 | 6-33447869-G-A | 4 | 2.58e-6 | -5.259 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -3.20 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2201 | 0.0936 | 0 | 2 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||
| c.3872T>A | L1291Q 2D AISynGAP1 missense variant L1291Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is equivocal (two benign, two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence is split, with an equal number of benign and pathogenic calls and no decisive high‑accuracy consensus. Consequently, the variant’s likely effect remains uncertain; it is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -4.450 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -4.18 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1052 | 0.1049 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3872T>G | L1291R 2D AIThe SynGAP1 missense variant L1291R is not reported in ClinVar and is present in gnomAD (ID 6‑33447920‑T‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta results are unavailable. Overall, the majority of conventional predictors indicate a pathogenic effect, whereas the single high‑accuracy tool suggests benign. No ClinVar annotation contradicts these findings. Thus, based on the collective evidence, the variant is most likely pathogenic, though the high‑accuracy prediction introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447920-T-G | 1 | 6.44e-7 | -3.977 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.287 | Likely Benign | -4.29 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1160 | 0.1049 | -2 | -3 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.3874C>T | L1292F 2D AIThe SynGAP1 missense variant L1292F is reported in gnomAD (ID 6‑33447922‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | 6-33447922-C-T | -5.759 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.88 | Neutral | 0.611 | Possibly Damaging | 0.329 | Benign | 2.49 | Pathogenic | 0.03 | Affected | 3.77 | 5 | 0.0707 | 0.2799 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3890G>C | R1297T 2D  AIThe SynGAP1 missense variant R1297T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: seven tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, FATHMM) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.941 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -2.95 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.49 | Pathogenic | 0.08 | Tolerated | 0.1634 | 0.2972 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1093G>C | V365L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity; only FoldX and Rosetta report uncertain stability changes, which are treated as unavailable evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect on protein folding stability. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||
| c.1093G>T | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is catalogued in gnomAD (ID 6‑33437998‑G‑T) but has no ClinVar entry. Across the available in‑silico predictors, the majority (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classify the change as benign; only FoldX and Rosetta report uncertain stability effects, which are treated as unavailable evidence. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from the unanimous benign vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Consequently, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | 6-33437998-G-T | 5 | 3.31e-6 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||
| c.1900G>C | A634P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -15.372 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.17 | Destabilizing | 0.2 | 7.72 | Destabilizing | 5.95 | Destabilizing | 1.39 | Destabilizing | 0.745 | Likely Pathogenic | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.2090 | 0.3429 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2207G>A | R736H 2D AIThe SynGAP1 missense variant R736H is listed in ClinVar (ID 1351080.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441672‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign. Foldetta results are not available. Overall, the majority of computational evidence indicates a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | Uncertain | 1 | 6-33441672-G-A | 6 | 3.72e-6 | -5.409 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.12 | Neutral | 0.004 | Benign | 0.001 | Benign | 2.50 | Benign | 0.00 | Affected | 4.07 | 3 | 0.2846 | 0.0921 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.2207G>C | R736P 2D AIThe SynGAP1 missense variant R736P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for R736P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | -5.246 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.83 | Neutral | 0.966 | Probably Damaging | 0.638 | Possibly Damaging | 2.50 | Benign | 0.00 | Affected | 0.2396 | 0.3237 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2260G>A | E754K 2D AIThe SynGAP1 missense variant E754K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus among in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, whereas polyPhen‑2 HumDiv and AlphaMissense‑Default predict pathogenicity; ESM1b remains uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign according to the aggregate predictions, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -7.620 | In-Between | 0.610 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | -1.33 | Neutral | 0.801 | Possibly Damaging | 0.412 | Benign | 2.50 | Benign | 0.26 | Tolerated | 0.2159 | 0.7136 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.2360C>G | P787R 2D AIThe SynGAP1 missense variant P787R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, whereas the single high‑accuracy tool indicates benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.013 | Likely Benign | 0.784 | Likely Pathogenic | Likely Benign | 0.268 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.50 | Benign | 0.03 | Affected | 0.1373 | 0.2741 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2426G>T | S809I 2D AIThe SynGAP1 missense variant S809I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from standard in silico predictors shows a split: six tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while two (SIFT, AlphaMissense‑Default) predict pathogenicity; ESM1b is uncertain. High‑accuracy assessment further supports a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign classification, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.708 | In-Between | 0.632 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.93 | Neutral | 0.065 | Benign | 0.022 | Benign | 2.50 | Benign | 0.01 | Affected | 0.1039 | 0.5984 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2464A>C | T822P 2D  AIThe SynGAP1 missense variant T822P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T822P. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -3.961 | Likely Benign | 0.737 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.50 | Benign | 0.09 | Tolerated | 0.2437 | 0.5044 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2465C>G | T822R 2D  AIThe SynGAP1 missense variant T822R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie and therefore unavailable; Foldetta predictions are not provided. Overall, the balance of evidence (five pathogenic versus three benign predictions) suggests the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | 0.414 | Likely Benign | 0.952 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -2.74 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.50 | Benign | 0.05 | Affected | 0.1182 | 0.3439 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2506A>T | S836C 2D AIThe SynGAP1 missense variant S836C is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -7.859 | In-Between | 0.208 | Likely Benign | Likely Benign | 0.184 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.923 | Probably Damaging | 2.50 | Benign | 0.04 | Affected | 0.0834 | 0.5468 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2590G>T | A864S 2D  AIThe SynGAP1 missense variant A864S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | -3.169 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.035 | Likely Benign | 0.08 | Neutral | 0.112 | Benign | 0.039 | Benign | 2.50 | Benign | 0.16 | Tolerated | 0.2792 | 0.6196 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2686G>T | G896C 2D  AIThe SynGAP1 missense variant G896C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -5.607 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -2.59 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.50 | Benign | 0.10 | Tolerated | 0.1270 | 0.4369 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2692T>A | S898T 2D AIThe SynGAP1 missense variant S898T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.910 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.33 | Neutral | 0.992 | Probably Damaging | 0.814 | Possibly Damaging | 2.50 | Benign | 0.78 | Tolerated | 0.1833 | 0.6209 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2954G>T | S985I 2D AIThe SynGAP1 missense variant S985I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that S985I is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -7.858 | In-Between | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | -2.78 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1367 | 0.5206 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3008G>T | S1003I 2D AIThe SynGAP1 missense variant S1003I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign votes); and Foldetta (combining FoldX‑MD and Rosetta) has no available output. Based on the overall distribution of predictions, the variant is most likely pathogenic. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -8.952 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.189 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1294 | 0.5735 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3027G>C | E1009D 2D AIThe SynGAP1 missense variant E1009D is reported in gnomAD (ID 6‑33443579‑G‑C) but has no ClinVar entry. All in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign effect, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | 6-33443579-G-C | 1 | 6.20e-7 | -2.958 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.37 | Neutral | 0.011 | Benign | 0.017 | Benign | 2.50 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2077 | 0.4817 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3027G>T | E1009D 2D AIThe SynGAP1 missense variant E1009D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -2.958 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.37 | Neutral | 0.011 | Benign | 0.017 | Benign | 2.50 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2077 | 0.4817 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3046G>A | D1016N 2D AIThe SynGAP1 missense variant D1016N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 assessments therefore indicate a benign prediction: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and no Foldetta data is available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.674 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.123 | Likely Benign | -2.12 | Neutral | 0.856 | Possibly Damaging | 0.723 | Possibly Damaging | 2.50 | Benign | 0.01 | Affected | 0.1989 | 0.7529 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3047A>C | D1016A 2D  AIThe SynGAP1 D1016A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the functional impact uncertain. **Based on the current predictions, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which has no entry for this variant.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -2.120 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.248 | Likely Benign | -2.71 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 2.50 | Benign | 0.02 | Affected | 0.4040 | 0.6760 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3049T>A | F1017I 2D  AIThe SynGAP1 missense variant F1017I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of conventional tools (5 pathogenic vs 4 benign) lean toward pathogenicity, but the single high‑accuracy benign prediction introduces uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -3.244 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.55 | Deleterious | 0.951 | Possibly Damaging | 0.710 | Possibly Damaging | 2.50 | Benign | 0.05 | Affected | 0.2050 | 0.1969 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3059G>T | R1020L 2D AISynGAP1 missense variant R1020L 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, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic effect, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | Uncertain | 1 | -6.031 | Likely Benign | 0.907 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -4.03 | Deleterious | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1898 | 0.5214 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.3108G>C | Q1036H 2D AIThe SynGAP1 missense variant Q1036H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -4.189 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.18 | Neutral | 0.977 | Probably Damaging | 0.615 | Possibly Damaging | 2.50 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.1641 | 0.4835 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3108G>T | Q1036H 2D AIThe SynGAP1 missense variant Q1036H is listed in gnomAD (ID 6‑33443660‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | 6-33443660-G-T | 1 | 6.20e-7 | -4.189 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.18 | Neutral | 0.977 | Probably Damaging | 0.615 | Possibly Damaging | 2.50 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.1641 | 0.4835 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||
| c.3149G>A | G1050E 2D AIThe SynGAP1 missense variant G1050E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -8.175 | Likely Pathogenic | 0.266 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.28 | Neutral | 0.411 | Benign | 0.171 | Benign | 2.50 | Benign | 0.08 | Tolerated | 0.1418 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.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 | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | 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 | 0.2942 | 0.3174 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3337G>T | G1113C 2D AIThe SynGAP1 missense variant G1113C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -7.917 | In-Between | 0.128 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.64 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.50 | Benign | 0.06 | Tolerated | 0.1325 | 0.4956 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3506A>C | E1169A 2D AIThe SynGAP1 missense variant E1169A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote method from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the consensus of benign‑predicting tools and the SGM‑Consensus outcome, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -2.132 | Likely Benign | 0.901 | Likely Pathogenic | Ambiguous | 0.217 | Likely Benign | -2.46 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.3714 | 0.6293 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3622C>G | R1208G 2D AIThe SynGAP1 missense variant R1208G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.566942 | Binding | 0.899 | 0.569 | 0.375 | -12.261 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -4.66 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.3287 | 0.2847 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3661C>T | R1221W 2D AIThe SynGAP1 missense variant R1221W is listed in ClinVar with an uncertain significance (ClinVar ID 1050818.0) and is present in the gnomAD database (gnomAD ID 6‑33446653‑C‑T). Functional prediction tools show a split assessment: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy analyses further refine the picture: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—deems it likely pathogenic. No Foldetta stability assessment is available for this residue. Overall, the majority of computational evidence points toward a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than a definitive benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | Conflicting | 3 | 6-33446653-C-T | 1 | 6.20e-7 | -10.938 | Likely Pathogenic | 0.651 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | -4.57 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1242 | 0.2585 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||
| c.3751C>G | Q1251E 2D AIThe SynGAP1 missense variant Q1251E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two uncertain and two benign calls, and Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -7.836 | In-Between | 0.499 | Ambiguous | Likely Benign | 0.183 | Likely Benign | -2.26 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1281 | 0.1266 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3752A>G | Q1251R 2D AIThe SynGAP1 missense variant Q1251R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -9.456 | Likely Pathogenic | 0.890 | Likely Pathogenic | Ambiguous | 0.236 | Likely Benign | -2.92 | Deleterious | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1257 | 0.1224 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||
| c.3821G>T | R1274L 2D AIThe SynGAP1 missense variant R1274L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the majority of reliable predictors and the high‑accuracy consensus favor a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | -5.318 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.165 | Likely Benign | -4.48 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.1657 | 0.3006 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3891G>C | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that R1297S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3891G>T | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly suggests that R1297S is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.1880C>G | A627G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect comprise SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -11.716 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.38 | Ambiguous | 0.1 | 2.07 | Destabilizing | 1.73 | Ambiguous | 1.25 | Destabilizing | 0.458 | Likely Benign | -3.96 | Deleterious | 0.997 | Probably Damaging | 0.876 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1921 | 0.2990 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1900G>A | A634T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, while only FATHMM predicts benign. Two tools give uncertain results: AlphaMissense‑Optimized and Foldetta. High‑accuracy assessment shows that the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic classification, whereas AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for A634T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -12.451 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.56 | Destabilizing | 0.1 | 1.11 | Ambiguous | 1.84 | Ambiguous | 1.34 | Destabilizing | 0.603 | Likely Pathogenic | -3.98 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1397 | 0.5240 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2206C>G | R736G 2D AIThe SynGAP1 missense variant R736G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv and SIFT predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | -4.100 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -2.05 | Neutral | 0.653 | Possibly Damaging | 0.361 | Benign | 2.51 | Benign | 0.00 | Affected | 0.3708 | 0.2554 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2234C>G | P745R 2D AIThe SynGAP1 missense variant P745R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of computational evidence points to a benign effect for P745R, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -4.564 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1571 | 0.2852 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2425A>C | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2426G>A | S809N 2D AIThe SynGAP1 missense variant S809N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for S809N, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -5.308 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.12 | Neutral | 0.784 | Possibly Damaging | 0.316 | Benign | 2.51 | Benign | 0.04 | Affected | 0.1363 | 0.5028 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.2427C>A | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>G | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2465C>A | T822K 2D  AIThe SynGAP1 missense variant T822K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of conventional tools lean toward a benign interpretation, but the high‑accuracy AlphaMissense‑Optimized prediction contradicts this. Because ClinVar has no entry for this variant, there is no existing clinical classification to conflict with; thus, the variant is most likely benign based on the preponderance of evidence, though high‑accuracy predictions remain inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -1.814 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | -2.25 | Neutral | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 2.51 | Benign | 0.07 | Tolerated | 0.1369 | 0.3552 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2477A>G | D826G 2D AIThe SynGAP1 D826G missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.310 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.323 | Likely Benign | -2.94 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.4251 | 0.7480 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2507G>T | S836I 2D AIThe SynGAP1 missense variant S836I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows five tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, SIFT) predict pathogenicity. Two additional predictors (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessment further indicates a benign prediction from AlphaMissense‑Optimized; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (one benign, one pathogenic, two uncertain). Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar annotation. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -7.751 | In-Between | 0.517 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -3.33 | Deleterious | 0.057 | Benign | 0.053 | Benign | 2.51 | Benign | 0.03 | Affected | 0.0756 | 0.5023 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2522T>G | V841G 2D  AIThe SynGAP1 missense variant V841G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, whereas the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity. 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 pathogenic effect for V841G, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -10.054 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.288 | Likely Benign | -4.11 | Deleterious | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.2351 | 0.2422 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2603A>G | D868G 2D AIThe SynGAP1 missense variant D868G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM Consensus) – derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -2.218 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -2.71 | Deleterious | 0.986 | Probably Damaging | 0.860 | Possibly Damaging | 2.51 | Benign | 0.21 | Tolerated | 0.4658 | 0.6414 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2723A>C | Q908P 2D AIThe SynGAP1 missense variant Q908P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for Q908P, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.446 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -0.59 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.51 | Benign | 0.11 | Tolerated | 0.2379 | 0.5121 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2953A>G | S985G 2D AIThe SynGAP1 missense variant S985G is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is not available. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the majority of reliable predictors and the SGM‑Consensus support a benign classification. The variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.151 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -2.29 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.2684 | 0.4540 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3008G>C | S1003T 2D AIThe SynGAP1 missense variant S1003T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of pathogenic predictors—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT—suggest a damaging impact. The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and no Foldetta data is present. Overall, the computational evidence supports a benign classification, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.140 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.115 | Likely Benign | -1.04 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.1864 | 0.6227 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3029T>C | F1010S 2D AIThe SynGAP1 missense variant F1010S is listed in gnomAD (ID 6‑33443581‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the balance of evidence, including the high‑accuracy benign predictions and the consensus benign call, indicates that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | 6-33443581-T-C | -1.722 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -1.97 | Neutral | 0.994 | Probably Damaging | 0.892 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 3.77 | 5 | 0.4196 | 0.0775 | -2 | -3 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||||
| c.3049T>G | F1017V 2D  AIThe SynGAP1 missense variant F1017V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F1017V, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.517 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.97 | Deleterious | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1964 | 0.2137 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3064C>T | L1022F 2D AIThe SynGAP1 missense variant L1022F is reported in gnomAD (variant ID 6‑33443616‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | 6-33443616-C-T | 2 | 1.24e-6 | -5.035 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.84 | Neutral | 0.971 | Probably Damaging | 0.801 | Possibly Damaging | 2.51 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.0730 | 0.4231 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||
| c.3065T>G | L1022R 2D AIThe SynGAP1 missense variant L1022R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L1022R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.875 | Likely Benign | 0.659 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | -1.96 | Neutral | 0.986 | Probably Damaging | 0.894 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1279 | 0.1387 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>C | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>T | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3505G>A | E1169K 2D AISynGAP1 missense variant E1169K is listed in gnomAD (ID 6‑33444540‑G‑A) but has no ClinVar record. Functional prediction tools fall into two groups: benign predictions come from SGM‑Consensus, REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign. Foldetta stability analysis is unavailable. Overall, the evidence is split evenly, with one high‑accuracy tool supporting pathogenicity and the consensus tool supporting benignity. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status, which has no entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | 6-33444540-G-A | 1 | 6.20e-7 | -3.335 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.185 | Likely Benign | -1.81 | Neutral | 0.997 | Probably Damaging | 0.898 | Possibly Damaging | 2.51 | Benign | 0.00 | Affected | 3.88 | 3 | 0.1969 | 0.6422 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.3506A>T | E1169V 2D AIThe SynGAP1 E1169V missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic signal: AlphaMissense‑Optimized is pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive (2 pathogenic vs 2 benign), and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence (seven pathogenic vs three benign predictions) indicates that E1169V is most likely pathogenic. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -2.482 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | -2.94 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.0581 | 0.7028 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3623G>T | R1208L 2D AIThe SynGAP1 missense variant R1208L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that R1208L is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.604312 | Disordered | 0.566942 | Binding | 0.899 | 0.569 | 0.375 | -10.576 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.204 | Likely Benign | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1621 | 0.3816 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3651A>C | E1217D 2D AIThe SynGAP1 missense variant E1217D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence points to a benign impact for E1217D, and this conclusion is consistent with the absence of any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.493043 | Uncertain | 0.877 | 0.563 | 0.250 | -5.983 | Likely Benign | 0.705 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -2.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.1745 | 0.3146 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3651A>T | E1217D 2D AIThe SynGAP1 missense variant E1217D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence points to a benign impact for E1217D, and this conclusion is consistent with the absence of any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.493043 | Uncertain | 0.877 | 0.563 | 0.250 | -5.983 | Likely Benign | 0.705 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -2.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.1745 | 0.3146 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3682G>A | E1228K 2D AIThe SynGAP1 E1228K missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -2.913 | Likely Benign | 0.533 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -2.17 | Neutral | 0.835 | Possibly Damaging | 0.468 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1673 | 0.4046 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3684A>C | E1228D 2D AIThe SynGAP1 missense variant E1228D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -4.788 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -1.89 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1667 | 0.2610 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3684A>T | E1228D 2D AIThe SynGAP1 missense variant E1228D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for E1228D, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -4.788 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -1.89 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1667 | 0.2610 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3712C>A | Q1238K 2D  AIThe SynGAP1 missense variant Q1238K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | -8.631 | Likely Pathogenic | 0.513 | Ambiguous | Likely Benign | 0.195 | Likely Benign | -1.70 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.51 | Benign | 0.30 | Tolerated | 0.1345 | 0.3494 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3776T>A | I1259N 2D  AIThe SynGAP1 missense variant I1259N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: 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) all indicate likely pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also reports a likely pathogenic classification. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for I1259N. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -10.979 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.459 | Likely Benign | -3.55 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.0799 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3823C>T | R1275W 2D AIThe SynGAP1 missense variant R1275W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447871‑C‑T). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a split vote (2 pathogenic, 1 benign, 1 uncertain). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the balance of evidence leans toward a pathogenic classification, and this assessment does not contradict ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | 6-33447871-C-T | 3 | 1.93e-6 | -9.895 | Likely Pathogenic | 0.513 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.875 | Possibly Damaging | 2.51 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1269 | 0.2372 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.1582C>G | P528A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, while the remaining pathogenic‑predicting tools are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy methods give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.562 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 1.57 | Ambiguous | 0.1 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.69 | Ambiguous | 0.548 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3146 | 0.3914 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1582C>T | P528S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No folding‑stability metrics (FoldX, Rosetta, premPS) provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.729 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.58 | Ambiguous | 0.80 | Ambiguous | 0.617 | Likely Pathogenic | -7.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3115 | 0.3982 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.2164A>C | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools and the high‑accuracy methods lean toward a pathogenic effect. Thus, the variant is most likely pathogenic based on current predictions, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.306 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2166C>A | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.221 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2166C>G | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, based on the current computational predictions, the S722R variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.220 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2198A>C | Q733P 2D AIThe SynGAP1 missense variant Q733P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -4.249 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -1.91 | Neutral | 0.220 | Benign | 0.308 | Benign | 2.52 | Benign | 0.04 | Affected | 0.2182 | 0.3894 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2199G>C | Q733H 2D AIThe SynGAP1 missense variant Q733H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.741 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -2.47 | Neutral | 0.990 | Probably Damaging | 0.780 | Possibly Damaging | 2.52 | Benign | 0.02 | Affected | 0.1341 | 0.2263 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2199G>T | Q733H 2D AIThe SynGAP1 missense variant Q733H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q733H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.741 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -2.47 | Neutral | 0.990 | Probably Damaging | 0.780 | Possibly Damaging | 2.52 | Benign | 0.02 | Affected | 0.1341 | 0.2263 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2216A>C | E739A 2D AIThe SynGAP1 missense variant E739A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of evidence points to a benign impact. The variant’s predicted benign nature does not contradict any ClinVar annotation, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | -2.337 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.85 | Neutral | 0.625 | Possibly Damaging | 0.252 | Benign | 2.52 | Benign | 0.00 | Affected | 0.4643 | 0.7148 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| 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. | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | 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 | 0.1566 | 0.3375 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2233C>A | P745T 2D AIThe SynGAP1 missense variant P745T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -5.119 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.203 | Likely Benign | -2.78 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.02 | Affected | 0.1657 | 0.4593 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2249G>C | G750A 2D AIThe SynGAP1 missense variant G750A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.263 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.65 | Neutral | 0.996 | Probably Damaging | 0.887 | Possibly Damaging | 2.52 | Benign | 0.04 | Affected | 0.3683 | 0.4792 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2522T>A | V841E 2D  AIThe SynGAP1 missense variant V841E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction tools and high‑accuracy methods indicates that V841E is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -13.750 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | -3.13 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.0939 | 0.1656 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2824C>G | P942A 2D AIThe SynGAP1 missense variant P942A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -4.404 | Likely Benign | 0.047 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -0.90 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.52 | Benign | 0.00 | Affected | 0.3362 | 0.4621 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2953A>C | S985R 2D AIThe SynGAP1 missense variant S985R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Consequently, the evidence is split evenly between benign and pathogenic predictions, with no contradiction to ClinVar status. The variant’s impact remains uncertain, and no definitive benign or pathogenic classification can be assigned based solely on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.174 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2955T>A | S985R 2D AIThe SynGAP1 missense variant S985R has no ClinVar entry and is not reported in gnomAD. Consensus predictions from multiple in‑silico tools are split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which reports a likely benign outcome. Pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (a majority‑vote aggregator) predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are evenly divided, leaving the variant’s clinical significance uncertain; it does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2955T>G | S985R 2D AISynGAP1 missense variant S985R has no ClinVar record and is not present in gnomAD. Computational predictions are mixed: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy tools give a split result: AlphaMissense‑Optimized predicts pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely benign; Foldetta data are unavailable. Consequently, the variant’s predicted impact is ambiguous, with an equal number of benign and pathogenic scores. No ClinVar evidence contradicts these predictions. Thus, the variant is best classified as of uncertain significance, with no clear bias toward benign or pathogenic status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3059G>A | R1020Q 2D AIThe SynGAP1 missense variant R1020Q is catalogued in gnomAD (6‑33443611‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | 6-33443611-G-A | 2 | 1.24e-6 | -3.753 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.137 | Likely Benign | -2.19 | Neutral | 0.995 | Probably Damaging | 0.870 | Possibly Damaging | 2.52 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3050 | 0.2997 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||||
| c.3107A>T | Q1036L 2D  AIThe SynGAP1 missense variant Q1036L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome, with two benign votes versus one pathogenic and one uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -4.389 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -2.92 | Deleterious | 0.152 | Benign | 0.045 | Benign | 2.52 | Benign | 0.01 | Affected | 0.1069 | 0.5996 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3595G>A | E1199K 2D AIThe SynGAP1 missense variant E1199K (ClinVar ID 1026146.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33446587‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are not available. Overall, the majority of evidence points toward a pathogenic impact, which does not contradict the ClinVar Uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.538167 | Disordered | 0.444533 | Uncertain | 0.878 | 0.598 | 0.250 | Uncertain | 1 | 6-33446587-G-A | 1 | 6.20e-7 | -10.853 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.171 | Likely Benign | -2.26 | Neutral | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1871 | 0.4072 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||
| c.3597G>C | E1199D 2D AIThe SynGAP1 missense variant E1199D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.538167 | Disordered | 0.444533 | Uncertain | 0.878 | 0.598 | 0.250 | -10.917 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.234 | Likely Benign | -2.08 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1728 | 0.2146 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3597G>T | E1199D 2D AIThe SynGAP1 missense variant E1199D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.538167 | Disordered | 0.444533 | Uncertain | 0.878 | 0.598 | 0.250 | -10.917 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.236 | Likely Benign | -2.08 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1728 | 0.2146 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3662G>C | R1221P 2D AIThe SynGAP1 missense variant R1221P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the high‑accuracy tools points to a pathogenic effect for R1221P. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | -14.148 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.52 | Benign | 0.05 | Affected | 0.2002 | 0.3095 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.3698T>A | I1233N 2D AIThe SynGAP1 I1233N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -9.586 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.193 | Likely Benign | -4.36 | Deleterious | 0.995 | Probably Damaging | 0.913 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.0879 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3820C>A | R1274S 2D AIThe SynGAP1 missense variant R1274S is not reported in ClinVar (status: “None”) but is present in gnomAD (ID 6‑33447868‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | 6-33447868-C-A | -3.149 | Likely Benign | 0.830 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -3.19 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3056 | 0.1830 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.1138G>A | G380R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G380R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence (10 pathogenic vs. 4 benign) points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.205 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 5.94 | Destabilizing | 2.6 | 0.90 | Ambiguous | 3.42 | Destabilizing | 0.11 | Likely Benign | 0.640 | Likely Pathogenic | -0.86 | Neutral | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 0.1319 | 0.3956 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1138G>C | G380R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G380R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, Foldetta predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (10 pathogenic vs 4 benign) and the Foldetta result support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.205 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 5.94 | Destabilizing | 2.6 | 0.90 | Ambiguous | 3.42 | Destabilizing | 0.11 | Likely Benign | 0.619 | Likely Pathogenic | -0.86 | Neutral | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 0.1319 | 0.3956 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1139G>A | G380E 2D AIThe SynGAP1 missense variant G380E has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized classifies the variant as benign, Foldetta predicts a pathogenic impact on protein stability, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools (7 benign vs. 6 pathogenic) lean toward a benign interpretation, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.334 | Likely Pathogenic | 0.617 | Likely Pathogenic | Likely Benign | 6.25 | Destabilizing | 5.1 | -0.28 | Likely Benign | 2.99 | Destabilizing | 0.24 | Likely Benign | 0.582 | Likely Pathogenic | -0.86 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.53 | Benign | 0.03 | Affected | 0.1585 | 0.3741 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.2194A>T | R732W 2D AIThe SynGAP1 missense variant R732W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, five tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these computational findings. Thus, the variant is most likely pathogenic based on the current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -11.976 | Likely Pathogenic | 0.252 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -3.57 | Deleterious | 1.000 | Probably Damaging | 0.973 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.1332 | 0.2748 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2234C>A | P745H 2D AIThe SynGAP1 missense variant P745H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -5.569 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -2.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.53 | Benign | 0.00 | Affected | 0.1912 | 0.3403 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2234C>T | P745L 2D AIThe SynGAP1 missense variant P745L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -6.303 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.2205 | 0.5188 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2262G>C | E754D 2D AIThe SynGAP1 missense variant E754D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -2.360 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.53 | Benign | 0.45 | Tolerated | 0.1725 | 0.3983 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2262G>T | E754D 2D AIThe SynGAP1 missense variant E754D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -2.360 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.53 | Benign | 0.45 | Tolerated | 0.1725 | 0.3983 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2477A>C | D826A 2D AIThe SynGAP1 D826A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -5.590 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.307 | Likely Benign | -3.77 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.53 | Benign | 0.02 | Affected | 0.4463 | 0.7867 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2500A>G | M834V 2D AIThe SynGAP1 missense variant M834V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -2.345 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.10 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 0.2562 | 0.2705 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2723A>T | Q908L 2D AIThe SynGAP1 missense variant Q908L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -3.589 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.193 | Likely Benign | -1.40 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.05 | Affected | 0.0706 | 0.5655 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2803G>T | A935S 2D AIThe SynGAP1 missense variant A935S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for A935S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.980490 | Binding | 0.286 | 0.865 | 0.625 | -3.361 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.53 | Benign | 0.00 | Affected | 0.2719 | 0.5496 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2806G>T | A936S 2D AIThe SynGAP1 missense variant A936S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.973218 | Binding | 0.319 | 0.874 | 0.625 | -3.555 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.07 | Neutral | 0.022 | Benign | 0.008 | Benign | 2.53 | Benign | 0.11 | Tolerated | 0.2675 | 0.5300 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3043A>C | T1015P 2D AIThe SynGAP1 missense variant T1015P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for T1015P, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -1.796 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -0.15 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.53 | Benign | 0.18 | Tolerated | 0.2176 | 0.4504 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3044C>T | T1015I 2D  AIThe SynGAP1 missense variant T1015I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for T1015I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -4.713 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.06 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.53 | Benign | 0.07 | Tolerated | 0.1232 | 0.4871 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3067T>G | S1023A 2D AIThe SynGAP1 missense variant S1023A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of pathogenic predictors—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT—suggest a damaging impact. The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy tools therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and no Foldetta data is available. Overall, the computational evidence supports a benign classification, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -6.031 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.098 | Likely Benign | -1.59 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.04 | Affected | 0.4427 | 0.4386 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3077A>C | D1026A 2D AIThe SynGAP1 D1026A variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie, and Foldetta results are not available. Overall, the majority of standard tools favor a benign interpretation, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.211 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.070 | Likely Benign | -2.69 | Deleterious | 0.112 | Benign | 0.061 | Benign | 2.53 | Benign | 0.02 | Affected | 0.3392 | 0.5279 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3101C>T | P1034L 2D AIThe SynGAP1 missense variant P1034L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default is uncertain. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that P1034L is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.204 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -3.24 | Deleterious | 0.001 | Benign | 0.005 | Benign | 2.53 | Benign | 0.01 | Affected | 0.2267 | 0.6937 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| 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). Consensus among most in silico predictors leans toward a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all report benign. In contrast, SIFT and ESM1b predict pathogenicity, while AlphaMissense‑Default remains uncertain. High‑accuracy assessment consolidates this view: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its influence is unavailable. Overall, the preponderance of computational evidence supports a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | Conflicting | 2 | 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 | 0.1052 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3175G>C | G1059R 2D AIThe SynGAP1 missense variant G1059R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all predict a benign effect, whereas SIFT and ESM1b predict pathogenicity; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also returns a benign prediction. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence points to a benign impact for G1059R, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -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 | 0.1052 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3175G>T | G1059W 2D  AIThe SynGAP1 missense variant G1059W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -11.549 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.0925 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3176G>A | G1059E 2D AIThe SynGAP1 missense variant G1059E is reported in gnomAD (variant ID 6‑33443728‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—SIFT and ESM1b—predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | 6-33443728-G-A | 1 | 6.22e-7 | -10.459 | Likely Pathogenic | 0.297 | Likely Benign | Likely Benign | 0.390 | Likely Benign | -0.71 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1464 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3226T>G | L1076V 2D AIThe SynGAP1 missense variant L1076V is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -3.615 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.56 | Neutral | 0.995 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.11 | Tolerated | 0.1632 | 0.3781 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>T | Q1107L 2D AIThe SynGAP1 missense variant Q1107L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.785 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -3.27 | Deleterious | 0.006 | Benign | 0.004 | Benign | 2.53 | Benign | 0.01 | Affected | 0.0820 | 0.6447 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3338G>T | G1113V 2D AIThe SynGAP1 missense variant G1113V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -5.708 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.98 | Neutral | 0.827 | Possibly Damaging | 0.456 | Possibly Damaging | 2.53 | Benign | 0.11 | Tolerated | 0.1333 | 0.4224 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3698T>G | I1233S 2D  AIThe SynGAP1 missense variant I1233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas the majority of other predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus likewise indicates likely pathogenic. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -8.066 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.184 | Likely Benign | -3.60 | Deleterious | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.2848 | 0.0910 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3751C>A | Q1251K 2D AIThe SynGAP1 missense variant Q1251K is catalogued in gnomAD (ID 6‑33446743‑C‑A) but has no ClinVar entry. Functional prediction tools show a split: benign calls from REVEL and FATHMM, whereas the majority—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—label it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized rates the variant as Uncertain, SGM‑Consensus remains Likely Pathogenic, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | 6-33446743-C-A | 1 | 6.20e-7 | -11.113 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 0.208 | Likely Benign | -2.92 | Deleterious | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.53 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1418 | 0.2635 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||
| c.3776T>G | I1259S 2D AIThe SynGAP1 missense variant I1259S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled “Likely Pathogenic.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -12.269 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.426 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.3004 | 0.1110 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3824G>C | R1275P 2D AIThe SynGAP1 missense variant R1275P is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447872‑G‑C). Prediction tools that agree on a benign effect are REVEL and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, as there is no contradictory status to report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | 6-33447872-G-C | -7.155 | In-Between | 0.823 | Likely Pathogenic | Ambiguous | 0.145 | Likely Benign | -3.55 | Deleterious | 0.966 | Probably Damaging | 0.651 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2211 | 0.3083 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||
| c.3871C>A | L1291M 2D AIThe SynGAP1 missense variant L1291M is reported in gnomAD (ID 6‑33447919‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four benign predictors) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447919-C-A | -5.625 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.93 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.53 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0767 | 0.2973 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.1139G>T | G380V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G380V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions are reported by REVEL, FoldX, polyPhen‑2 HumDiv, and SIFT; Rosetta is uncertain. The SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority of the four high‑accuracy tools) is benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -6.234 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 7.60 | Destabilizing | 2.5 | 1.75 | Ambiguous | 4.68 | Destabilizing | -0.17 | Likely Benign | 0.574 | Likely Pathogenic | -0.70 | Neutral | 0.816 | Possibly Damaging | 0.210 | Benign | 2.54 | Benign | 0.02 | Affected | 0.1618 | 0.3708 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1351C>G | L451V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; and Foldetta predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L451V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -10.732 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 2.83 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.32 | Destabilizing | 1.39 | Destabilizing | 0.325 | Likely Benign | -2.90 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1065 | 0.2856 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1393C>A | L465I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L465I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score classifies the variant as benign, whereas the Foldetta stability assessment is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split. Overall, the evidence is mixed; the balance of predictions leans toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -9.672 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 1.21 | Ambiguous | 0.1 | 1.27 | Ambiguous | 1.24 | Ambiguous | 0.78 | Ambiguous | 0.258 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0967 | 0.3539 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1802C>A | A601E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Conflicting | 2 | -16.752 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 6.68 | Destabilizing | 0.8 | 5.76 | Destabilizing | 6.22 | Destabilizing | 1.24 | Destabilizing | 0.588 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1346 | 0.1444 | 0 | -1 | -5.3 | 58.04 | 240.0 | -82.3 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | X | Potentially Pathogenic | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, the carboxylate group of Glu601 faces the inter-helix space and is forced to shift slightly away from the hydrophobic niche. Additionally, in two of the simulations, Glu601 forms a salt bridge with Arg499, causing the otherwise stable salt bridge between Arg499 and Glu496 at the outer surface of an α helix (res. Leu489-Glu519) to break due to the residue swap.These effects suggest that the protein folding process could be seriously affected. Moreover, due to its location at the GAP-Ras interface, it could also impact the complex formation with the GTPase. | ||||||||||||||
| c.2233C>T | P745S 2D AIThe SynGAP1 missense variant P745S is reported in gnomAD (variant ID 6-33441698-C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and 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) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods points to a benign effect for P745S, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | 6-33441698-C-T | 1 | 6.19e-7 | -4.300 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.160 | Likely Benign | -2.32 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.05 | Affected | 4.32 | 2 | 0.3397 | 0.3882 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2476G>A | D826N 2D AIThe SynGAP1 missense variant D826N has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on benign effects include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Given the balance of evidence, the majority of high‑confidence predictions and the SGM consensus favor a benign outcome. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -3.663 | Likely Benign | 0.907 | Likely Pathogenic | Ambiguous | 0.154 | Likely Benign | -2.24 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1520 | 0.8248 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2506A>C | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence (five benign versus three pathogenic predictions, with the high‑accuracy consensus leaning benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2506A>G | S836G 2D AIThe SynGAP1 missense variant S836G is listed in ClinVar (ID 537003.0) with an uncertain significance annotation and is observed in the gnomAD database (variant ID 6‑33443058‑A‑G). Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. Foldetta, a protein‑folding stability predictor, did not return a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not conflict with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | Uncertain | 1 | 6-33443058-A-G | 4 | 2.48e-6 | -4.749 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.65 | Neutral | 0.006 | Benign | 0.019 | Benign | 2.54 | Benign | 0.39 | Tolerated | 3.77 | 5 | 0.2567 | 0.4089 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||
| c.2508T>A | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2508T>G | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Grouping by agreement, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Benign, and no Foldetta stability data are available. Overall, the preponderance of evidence leans toward a benign effect for S836R, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2521G>A | V841M 2D AISynGAP1 variant V841M is listed in ClinVar with an uncertain significance and is present in gnomAD (6-33443073-G-A). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The ESM1b score is inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta stability analysis is unavailable. Taken together, the majority of evidence, including the high‑accuracy tools, points to a benign effect for V841M. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | Uncertain | 1 | 6-33443073-G-A | 3 | 1.86e-6 | -7.000 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.119 | Likely Benign | -0.74 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0707 | 0.3937 | 1 | 2 | -2.3 | 32.06 | |||||||||||||||||||||||||||||||||
| c.2603A>C | D868A 2D AIThe SynGAP1 D868A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the balance of evidence—including the benign prediction from the most accurate AlphaMissense‑Optimized model and the majority of benign calls—suggests that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -2.764 | Likely Benign | 0.702 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -2.75 | Deleterious | 0.972 | Probably Damaging | 0.760 | Possibly Damaging | 2.54 | Benign | 0.21 | Tolerated | 0.4590 | 0.6990 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2627C>G | S876W 2D  AIThe SynGAP1 missense variant S876W is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33443179‑C‑G). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM‑Consensus indicates a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict ClinVar status, as no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | 6-33443179-C-G | 1 | 6.20e-7 | -9.305 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0964 | 0.6700 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2675C>G | S892C 2D AIThe SynGAP1 missense variant S892C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for S892C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -6.855 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 0.1189 | 0.5323 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2687G>C | G896A 2D AIThe SynGAP1 missense variant G896A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and there is no conflict with ClinVar status because no ClinVar claim exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -3.562 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.95 | Neutral | 0.561 | Possibly Damaging | 0.139 | Benign | 2.54 | Benign | 0.79 | Tolerated | 0.3799 | 0.4963 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2755C>A | Q919K 2D AIThe SynGAP1 missense variant Q919K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the majority of evidence supports a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -4.357 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -1.43 | Neutral | 0.771 | Possibly Damaging | 0.412 | Benign | 2.54 | Benign | 0.21 | Tolerated | 0.1950 | 0.4000 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2765G>C | R922P 2D AIThe SynGAP1 missense variant R922P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R922P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -2.502 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | -1.36 | Neutral | 0.998 | Probably Damaging | 0.942 | Probably Damaging | 2.54 | Benign | 0.10 | Tolerated | 0.2391 | 0.4966 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2799C>A | H933Q 2D  AIThe SynGAP1 missense variant H933Q has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign (two benign versus one pathogenic vote). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -3.042 | Likely Benign | 0.410 | Ambiguous | Likely Benign | 0.211 | Likely Benign | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.54 | Benign | 0.53 | Tolerated | 0.1654 | 0.3938 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2799C>G | H933Q 2D AIThe SynGAP1 H933Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction between the predictions and ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -3.042 | Likely Benign | 0.410 | Ambiguous | Likely Benign | 0.210 | Likely Benign | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.54 | Benign | 0.53 | Tolerated | 0.1654 | 0.3938 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2871T>A | H957Q 2D AIThe SynGAP1 missense variant H957Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.304 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.87 | Neutral | 0.255 | Benign | 0.105 | Benign | 2.54 | Benign | 0.56 | Tolerated | 0.2227 | 0.4114 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2871T>G | H957Q 2D AIThe SynGAP1 missense variant H957Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | -6.304 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.87 | Neutral | 0.255 | Benign | 0.105 | Benign | 2.54 | Benign | 0.56 | Tolerated | 0.2227 | 0.4114 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2954G>C | S985T 2D AIThe SynGAP1 missense variant S985T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S985T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -5.658 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 0.1889 | 0.5844 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3044C>A | T1015N 2D  AIThe SynGAP1 missense variant T1015N is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -4.353 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.28 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.54 | Benign | 0.24 | Tolerated | 0.1688 | 0.4233 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3107A>G | Q1036R 2D AIThe SynGAP1 missense variant Q1036R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence points to a benign effect for Q1036R, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.816 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.083 | Likely Benign | -1.32 | Neutral | 0.292 | Benign | 0.071 | Benign | 2.54 | Benign | 0.04 | Affected | 0.1710 | 0.3071 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3142G>A | G1048R 2D AIThe SynGAP1 missense variant G1048R is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: pathogenic calls come from REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar, whereas benign calls are made by PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority, and AlphaMissense‑Optimized itself predicts benign. The SGM‑Consensus, which aggregates these four predictors, reports a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -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 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| 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 | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | 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 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3142G>T | G1048W 2D AIThe SynGAP1 missense variant G1048W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -8.803 | Likely Pathogenic | 0.340 | Likely Benign | Likely Benign | 0.498 | Likely Benign | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0852 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>A | G1048E 2D AIThe SynGAP1 missense variant G1048E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only REVEL predicts a pathogenic outcome, while ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -7.028 | In-Between | 0.331 | Likely Benign | Likely Benign | 0.529 | Likely Pathogenic | -0.62 | Neutral | 0.018 | Benign | 0.030 | Benign | 2.54 | Benign | 0.10 | Tolerated | 0.1444 | 0.4063 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>T | G1048V 2D AIThe SynGAP1 missense variant G1048V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -6.108 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.520 | Likely Pathogenic | -0.59 | Neutral | 0.958 | Probably Damaging | 0.787 | Possibly Damaging | 2.54 | Benign | 0.11 | Tolerated | 0.1312 | 0.3688 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3176G>T | G1059V 2D AIThe SynGAP1 missense variant G1059V is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy tools corroborate the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for G1059V, and this assessment does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -7.242 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.478 | Likely Benign | -0.82 | Neutral | 0.259 | Benign | 0.066 | Benign | 2.54 | Benign | 0.00 | Affected | 0.1462 | 0.3494 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3202T>G | L1068V 2D AIThe SynGAP1 missense variant L1068V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -5.325 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.58 | Neutral | 0.451 | Benign | 0.110 | Benign | 2.54 | Benign | 0.00 | Affected | 0.1619 | 0.4404 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3322A>C | S1108R 2D AISynGAP1 missense variant S1108R is not reported in ClinVar (status: None) and is absent from gnomAD (no entry). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive, as it yields a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence is mixed, with an equal number of benign and pathogenic calls and no high‑confidence consensus. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict the ClinVar status, which is unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.130 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3324C>A | S1108R 2D AISynGAP1 missense variant S1108R has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Consequently, the evidence is evenly divided, leaving the variant’s functional impact uncertain. The predictions do not contradict any ClinVar status, as none is available. Overall, the variant is most likely of uncertain significance rather than definitively benign or pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3324C>G | S1108R 2D AIThe SynGAP1 missense variant S1108R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, the computational evidence is balanced, providing no clear bias toward benign or pathogenic. Thus, the variant’s likely impact remains uncertain, and there is no contradiction with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3443T>G | M1148R 2D AIThe SynGAP1 missense variant M1148R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -2.303 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -1.77 | Neutral | 0.255 | Benign | 0.113 | Benign | 2.54 | Benign | 0.00 | Affected | 0.1624 | 0.0888 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3494C>G | S1165W 2D AIThe SynGAP1 missense variant S1165W has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of tools supporting benign versus pathogenic effects. Consequently, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -6.419 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -2.29 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0671 | 0.4807 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3623G>A | R1208Q 2D AIThe SynGAP1 missense variant R1208Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, and FATHMM, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie, and Foldetta data are unavailable. Overall, the majority of evidence points toward pathogenicity, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.604312 | Disordered | 0.566942 | Binding | 0.899 | 0.569 | 0.375 | -8.434 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.14 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.2683 | 0.2040 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3661C>G | R1221G 2D AIThe SynGAP1 missense variant R1221G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the majority of available predictions lean toward a benign impact, with no ClinVar evidence contradicting this assessment. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | -7.982 | In-Between | 0.552 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -3.55 | Deleterious | 0.992 | Probably Damaging | 0.900 | Possibly Damaging | 2.54 | Benign | 0.06 | Tolerated | 0.3185 | 0.2110 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3770C>G | S1257C 2D AIThe SynGAP1 missense variant S1257C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus score indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and ESM1b 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) also yields a likely benign verdict. Foldetta data are not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -7.741 | In-Between | 0.125 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -2.15 | Neutral | 0.028 | Benign | 0.027 | Benign | 2.54 | Benign | 0.05 | Affected | 0.0761 | 0.4780 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.3776T>C | I1259T 2D  AIThe SynGAP1 missense variant I1259T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign) and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs. three benign predictions) points to a pathogenic impact. The variant is most likely pathogenic based on current predictions, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -10.057 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.399 | Likely Benign | -2.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.0991 | 0.1051 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3823C>G | R1275G 2D AIThe SynGAP1 missense variant R1275G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for R1275G, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | -6.302 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -3.58 | Deleterious | 0.800 | Possibly Damaging | 0.277 | Benign | 2.54 | Benign | 0.01 | Affected | 0.3272 | 0.2486 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>C | N1306H 2D  AIThe SynGAP1 missense variant N1306H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is labeled “Likely Benign”). In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -2.949 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -3.42 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.1705 | 0.7846 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>T | N1306Y 2D  AIThe SynGAP1 missense variant N1306Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -4.193 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.273 | Likely Benign | -5.59 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.0732 | 0.6658 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.1802C>G | A601G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601G missense variant is listed in gnomAD (ID 6‑33440854‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The high‑accuracy consensus methods give a pathogenic verdict: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also pathogenic. AlphaMissense‑Default and premPS are uncertain, and no evidence is available from other folding‑stability tools. Overall, the preponderance of evidence points to a pathogenic impact for A601G, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | 6-33440854-C-G | 1 | 6.19e-7 | -11.772 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.03 | Destabilizing | 0.0 | 2.31 | Destabilizing | 2.17 | Destabilizing | 0.94 | Ambiguous | 0.511 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2337 | 0.4370 | 0 | 1 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1901C>T | A634V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, while only FATHMM predicts a benign outcome; Rosetta remains inconclusive. High‑accuracy assessments reinforce the pathogenic trend: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence supports a pathogenic effect for A634V, which is in contrast to its current ClinVar classification of uncertain significance. Therefore, the variant is most likely pathogenic, contradicting its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | Uncertain | 1 | -12.612 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.2 | 1.44 | Ambiguous | 2.06 | Destabilizing | 1.14 | Destabilizing | 0.631 | Likely Pathogenic | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.976 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 0.1215 | 0.4371 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| c.2195G>T | R732M 2D AIThe SynGAP1 missense variant R732M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta results are unavailable. Overall, the balance of evidence (5 benign vs 3 pathogenic predictions) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -9.956 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 0.098 | Likely Benign | -1.42 | Neutral | 0.840 | Possibly Damaging | 0.357 | Benign | 2.55 | Benign | 0.01 | Affected | 0.1432 | 0.2980 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2198A>T | Q733L 2D AIThe SynGAP1 missense variant Q733L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -3.465 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -2.04 | Neutral | 0.905 | Possibly Damaging | 0.408 | Benign | 2.55 | Benign | 1.00 | Tolerated | 0.0736 | 0.4291 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2215G>A | E739K 2D AIThe SynGAP1 missense variant E739K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | -5.420 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.107 | Likely Benign | -1.49 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.55 | Benign | 0.00 | Affected | 0.2697 | 0.7044 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2219G>C | R740P 2D AIThe SynGAP1 missense variant R740P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for R740P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | -4.163 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.55 | Benign | 0.02 | Affected | 0.2426 | 0.4338 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2233C>G | P745A 2D AIThe SynGAP1 missense variant P745A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for P745A, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -4.599 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -2.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.55 | Benign | 0.17 | Tolerated | 0.3424 | 0.3458 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2276T>A | M759K 2D AIThe SynGAP1 missense variant M759K (ClinVar ID 4178662) is listed as ClinVar status Uncertain and is not present 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, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar Uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | -5.670 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | 0.288 | Likely Benign | -1.86 | Neutral | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1338 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||
| c.2276T>G | M759R 2D AIThe SynGAP1 missense variant M759R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for M759R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.507 | Likely Benign | 0.531 | Ambiguous | Likely Benign | 0.244 | Likely Benign | -1.82 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1509 | 0.0637 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2498A>T | K833M 2D  AIThe SynGAP1 missense variant K833M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evaluated predictors (six benign vs. four pathogenic) support a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -3.234 | Likely Benign | 0.685 | Likely Pathogenic | Likely Benign | 0.181 | Likely Benign | -2.05 | Neutral | 0.997 | Probably Damaging | 0.954 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 0.0867 | 0.3652 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2542G>T | G848C 2D AIThe SynGAP1 missense variant G848C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -6.987 | Likely Benign | 0.248 | Likely Benign | Likely Benign | 0.237 | Likely Benign | -1.14 | Neutral | 0.998 | Probably Damaging | 0.922 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 0.1264 | 0.4400 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2590G>A | A864T 2D AIThe SynGAP1 missense variant A864T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | -4.314 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.016 | Likely Benign | -1.00 | Neutral | 0.224 | Benign | 0.113 | Benign | 2.55 | Benign | 0.10 | Tolerated | 0.1504 | 0.7485 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2591C>G | A864G 2D AIThe SynGAP1 missense variant A864G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions points to a benign effect, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | -3.662 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.55 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.55 | Benign | 0.16 | Tolerated | 0.2383 | 0.5388 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2602G>A | D868N 2D AIThe SynGAP1 D868N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and 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 predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.052 | Likely Benign | 0.419 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.01 | Neutral | 0.986 | Probably Damaging | 0.922 | Probably Damaging | 2.55 | Benign | 0.21 | Tolerated | 0.1977 | 0.7152 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2675C>A | S892Y 2D AIThe SynGAP1 missense variant S892Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) also predicts benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.696 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.29 | Neutral | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.55 | Benign | 0.00 | Affected | 0.0814 | 0.5051 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2675C>T | S892F 2D AIThe SynGAP1 missense variant S892F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.709 | Likely Benign | 0.605 | Likely Pathogenic | Likely Benign | 0.090 | Likely Benign | -3.07 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.55 | Benign | 0.00 | Affected | 0.0715 | 0.5124 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2764C>G | R922G 2D AIThe SynGAP1 missense variant R922G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the change is benign: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta data are missing. Overall, the preponderance of evidence points to a benign impact for R922G, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -2.490 | Likely Benign | 0.472 | Ambiguous | Likely Benign | 0.104 | Likely Benign | -1.48 | Neutral | 0.967 | Probably Damaging | 0.626 | Possibly Damaging | 2.55 | Benign | 0.10 | Tolerated | 0.3473 | 0.3768 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3076G>A | D1026N 2D AIThe SynGAP1 D1026N variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.166 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -2.07 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.55 | Benign | 0.01 | Affected | 0.1240 | 0.5060 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3260C>G | S1087C 2D AIThe SynGAP1 missense variant S1087C is catalogued in gnomAD (ID 6‑33443812‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-G | 1 | 6.34e-7 | -7.369 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -2.22 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.55 | Benign | 0.05 | Affected | 3.77 | 5 | 0.0979 | 0.6118 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.3271C>A | L1091I 2D AIThe SynGAP1 missense variant L1091I is reported in gnomAD (ID 6‑33443823‑C‑A) but has no ClinVar entry. Across the available in‑silico predictors, every tool classified the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all returned benign scores. No tool predicted pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this benign view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available for this variant. Overall, the computational evidence strongly supports a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | 6-33443823-C-A | -4.304 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.66 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.55 | Benign | 0.13 | Tolerated | 3.77 | 5 | 0.1073 | 0.3911 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.3320A>G | Q1107R 2D AIThe SynGAP1 missense variant Q1107R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -2.837 | Likely Benign | 0.394 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.76 | Neutral | 0.965 | Probably Damaging | 0.425 | Benign | 2.55 | Benign | 0.04 | Affected | 0.1482 | 0.3319 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3443T>A | M1148K 2D AIThe SynGAP1 missense variant M1148K is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -2.527 | Likely Benign | 0.624 | Likely Pathogenic | Likely Benign | 0.105 | Likely Benign | -1.58 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.55 | Benign | 0.00 | Affected | 0.1539 | 0.1056 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3493T>C | S1165P 2D AIThe SynGAP1 missense variant S1165P is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, whereas the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) indicate that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.476 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -1.87 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.55 | Benign | 0.23 | Tolerated | 0.2295 | 0.4930 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3662G>T | R1221L 2D AIThe SynGAP1 missense variant R1221L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is uncertain because it receives one benign, one pathogenic, and two uncertain votes. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the single high‑accuracy tool predicts benign and the consensus remains inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | -7.995 | In-Between | 0.480 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -3.71 | Deleterious | 0.992 | Probably Damaging | 0.866 | Possibly Damaging | 2.55 | Benign | 0.05 | Affected | 0.1557 | 0.3206 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3698T>C | I1233T 2D AIThe SynGAP1 missense variant I1233T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -6.470 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.142 | Likely Benign | -2.89 | Deleterious | 0.896 | Possibly Damaging | 0.596 | Possibly Damaging | 2.55 | Benign | 0.01 | Affected | 0.1018 | 0.1419 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3769T>C | S1257P 2D AIThe SynGAP1 missense variant S1257P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; Foldetta results are unavailable. Overall, the majority of computational evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -11.985 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -2.54 | Deleterious | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1656 | 0.4519 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||
| c.3770C>A | S1257Y 2D AIThe SynGAP1 missense variant S1257Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans pathogenic (2 pathogenic vs 1 benign). Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.632 | Likely Pathogenic | 0.399 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -2.65 | Deleterious | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.55 | Benign | 0.03 | Affected | 0.0480 | 0.4463 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3770C>T | S1257F 2D AIThe SynGAP1 missense variant S1257F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.584 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 0.141 | Likely Benign | -2.41 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.55 | Benign | 0.08 | Tolerated | 0.0453 | 0.4747 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3775A>T | I1259F 2D  AIThe SynGAP1 missense variant I1259F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized returns an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of evidence (five pathogenic vs. three benign) points toward a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -10.666 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.301 | Likely Benign | -1.68 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.55 | Benign | 0.03 | Affected | 0.0428 | 0.2563 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3824G>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. | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | 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 | 0.1687 | 0.3181 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||
| c.3866A>T | K1289M 2D AIThe SynGAP1 missense variant K1289M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the SGM consensus and AlphaMissense‑Optimized—points to a benign effect. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.372 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.071 | Likely Benign | -1.79 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.55 | Benign | 0.01 | Affected | 0.1015 | 0.2780 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.1139G>C | G380A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G380A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FoldX predicts a pathogenic outcome, while Rosetta and Foldetta are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta as uncertain. Overall, the overwhelming majority of evidence points to a benign effect, with no conflict with ClinVar status (which has no entry for this variant). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -6.433 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 3.11 | Destabilizing | 1.0 | -0.15 | Likely Benign | 1.48 | Ambiguous | -0.06 | Likely Benign | 0.422 | Likely Benign | -0.53 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.56 | Benign | 0.17 | Tolerated | 0.3915 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1801G>C | A601P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all report pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -14.584 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.90 | Destabilizing | 0.6 | 8.84 | Destabilizing | 6.87 | Destabilizing | 0.87 | Ambiguous | 0.713 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2176 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1801G>T | A601S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yields an uncertain result. Overall, more tools (six) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -11.248 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.21 | Ambiguous | 0.79 | Ambiguous | 0.541 | Likely Pathogenic | -2.99 | Deleterious | 0.983 | Probably Damaging | 0.993 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2732 | 0.4730 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1879G>A | A627T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. Two tools, premPS and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta also predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that A627T is most likely pathogenic, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -8.613 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 2.27 | Destabilizing | 0.3 | 2.33 | Destabilizing | 2.30 | Destabilizing | 0.80 | Ambiguous | 0.505 | Likely Pathogenic | -3.95 | Deleterious | 0.994 | Probably Damaging | 0.807 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1069 | 0.5403 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2194A>G | R732G 2D AIThe SynGAP1 R732G missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33441659‑A‑G). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, while the most accurate single predictor (AlphaMissense‑Optimized) suggests a benign outcome. Given the lack of ClinVar evidence, there is no contradiction; the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | 6-33441659-A-G | 1 | 6.20e-7 | -9.348 | Likely Pathogenic | 0.295 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.98 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.56 | Benign | 0.03 | Affected | 3.59 | 7 | 0.3080 | 0.2942 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2218C>G | R740G 2D AIThe SynGAP1 missense variant R740G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | -4.556 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -2.55 | Deleterious | 0.993 | Probably Damaging | 0.887 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 0.3739 | 0.3149 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2240T>A | V747E 2D AIThe SynGAP1 missense variant V747E is evaluated by multiple in silico tools. ClinVar has no entry for this change, and it is not reported in gnomAD. Consensus from the SGM‑Consensus algorithm classifies the variant as Likely Benign. When grouping predictions by agreement, benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign, and no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.594069 | Binding | 0.343 | 0.873 | 0.750 | -4.124 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -1.31 | Neutral | 0.917 | Possibly Damaging | 0.666 | Possibly Damaging | 2.56 | Benign | 0.00 | Affected | 0.0965 | 0.1559 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2240T>G | V747G 2D AIThe SynGAP1 missense variant V747G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta results are unavailable. Overall, the consensus of the available predictions indicates that V747G is most likely benign, and this conclusion does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.816150 | Disordered | 0.594069 | Binding | 0.343 | 0.873 | 0.750 | -3.883 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.22 | Neutral | 0.589 | Possibly Damaging | 0.917 | Probably Damaging | 2.56 | Benign | 0.00 | Affected | 0.1960 | 0.2374 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2502G>A | M834I 2D AIThe SynGAP1 missense variant M834I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2502G>C | M834I 2D AIThe SynGAP1 missense variant M834I is listed in ClinVar (ID 3007819.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the collective predictions indicate that M834I is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | Uncertain | 1 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2502G>T | M834I 2D AIThe SynGAP1 missense variant M834I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2507G>C | S836T 2D AIThe SynGAP1 missense variant S836T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -3.871 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.28 | Neutral | 0.901 | Possibly Damaging | 0.535 | Possibly Damaging | 2.56 | Benign | 0.36 | Tolerated | 0.1161 | 0.5326 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>C | S876P 2D AIThe SynGAP1 missense variant S876P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions indicates that S876P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.002 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -2.04 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.56 | Benign | 0.35 | Tolerated | 0.1979 | 0.6928 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2650C>T | R884W 2D AIThe SynGAP1 missense variant R884W is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443202‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta (protein‑folding stability) result is available for this variant. Overall, the majority of computational predictions, including the high‑accuracy tools, indicate that R884W is most likely benign, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | Uncertain | 1 | 6-33443202-C-T | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.151 | Likely Benign | 0.26 | Neutral | 0.995 | Probably Damaging | 0.812 | Possibly Damaging | 2.56 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1223 | 0.3304 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2662G>C | A888P 2D AIThe SynGAP1 missense variant A888P is reported in gnomAD (variant ID 6‑33443214‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for A888P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.575860 | Binding | 0.352 | 0.928 | 0.625 | 6-33443214-G-C | 5 | 3.10e-6 | -2.368 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.02 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1859 | 0.5764 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.2663C>A | A888D 2D AIThe SynGAP1 missense variant A888D is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while SIFT uniquely predicts it as pathogenic. The consensus prediction from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.575860 | Binding | 0.352 | 0.928 | 0.625 | -3.870 | Likely Benign | 0.526 | Ambiguous | Likely Benign | 0.078 | Likely Benign | -1.52 | Neutral | 0.077 | Benign | 0.097 | Benign | 2.56 | Benign | 0.00 | Affected | 0.1646 | 0.1386 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2704G>C | A902P 2D AIThe SynGAP1 missense variant A902P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A902P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -4.509 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.146 | Likely Benign | 0.09 | Neutral | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1694 | 0.5304 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>C | Q1021P 2D AIThe SynGAP1 missense variant Q1021P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1021P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -3.522 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -2.11 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.56 | Benign | 0.02 | Affected | 0.2022 | 0.4789 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3176G>C | G1059A 2D AIThe SynGAP1 missense variant G1059A is listed in ClinVar (ID 1420036.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443728‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of computational evidence supports a benign impact for G1059A, which does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | Uncertain | 1 | 6-33443728-G-C | 4 | 2.49e-6 | -6.754 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.329 | Likely Benign | -0.17 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3295 | 0.4944 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3259T>C | S1087P 2D AIThe SynGAP1 missense variant S1087P is reported in gnomAD (ID 6‑33443811‑T‑C) and has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443811-T-C | 1 | 6.34e-7 | -2.946 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -1.92 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.1803 | 0.5700 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.3260C>A | S1087Y 2D AIThe SynGAP1 missense variant S1087Y is catalogued in gnomAD (ID 6‑33443812‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-A | -4.194 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.41 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0671 | 0.5845 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.3260C>T | S1087F 2D AISynGAP1 missense variant S1087F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of reliable predictors and the two high‑accuracy tools suggest a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | Uncertain | 1 | -3.843 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -2.75 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0645 | 0.6029 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.3323G>C | S1108T 2D AIThe SynGAP1 missense variant S1108T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.710 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.49 | Neutral | 0.393 | Benign | 0.239 | Benign | 2.56 | Benign | 0.25 | Tolerated | 0.1304 | 0.5365 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3443T>C | M1148T 2D AIThe SynGAP1 missense variant M1148T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -0.972 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -1.50 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.56 | Benign | 0.00 | Affected | 0.2063 | 0.2214 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.3641G>T | R1214L 2D AIThe SynGAP1 missense variant R1214L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments are limited: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta data are unavailable. Overall, the majority of available predictions (four pathogenic versus three benign) suggest a pathogenic impact. This conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.497853 | Structured | 0.506868 | Binding | 0.903 | 0.566 | 0.375 | -7.058 | In-Between | 0.510 | Ambiguous | Likely Benign | 0.114 | Likely Benign | -3.65 | Deleterious | 0.992 | Probably Damaging | 0.828 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1497 | 0.2988 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3662G>A | R1221Q 2D AIThe SynGAP1 missense variant R1221Q is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446654‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, SGM Consensus is likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | Conflicting | 2 | 6-33446654-G-A | 4 | 2.48e-6 | -5.491 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.46 | Neutral | 0.836 | Possibly Damaging | 0.153 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.2093 | 0.1736 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||
| c.3697A>T | I1233F 2D AIThe SynGAP1 missense variant I1233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, more tools predict pathogenicity (five) than benignity (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -8.414 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -2.34 | Neutral | 0.968 | Probably Damaging | 0.713 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 0.0418 | 0.2731 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>G | E1296G 2D AIThe SynGAP1 missense variant E1296G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.864 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -5.10 | Deleterious | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.2971 | 0.5231 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3889A>G | R1297G 2D AIThe SynGAP1 missense variant R1297G is reported in gnomAD (ID 6‑33451763‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that R1297G is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451763-A-G | 3 | 1.86e-6 | -2.833 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -3.65 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.56 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3089 | 0.2400 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||
| c.3917A>T | N1306I 2D  AIThe SynGAP1 missense variant N1306I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.234 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -6.15 | Deleterious | 0.890 | Possibly Damaging | 0.761 | Possibly Damaging | 2.56 | Benign | 0.00 | Affected | 0.0837 | 0.6672 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.1801G>A | A601T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601T missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, whereas the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently flag the variant as deleterious. Two tools, FoldX and premPS, return uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -10.635 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 1.55 | Ambiguous | 0.1 | 2.66 | Destabilizing | 2.11 | Destabilizing | 0.76 | Ambiguous | 0.642 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.57 | Benign | 0.00 | Affected | 0.1564 | 0.5554 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2165G>C | S722T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722T is reported in gnomAD (6‑33441630‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while FoldX is uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441630-G-C | 1 | 6.20e-7 | -5.734 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | -0.32 | Likely Benign | 0.11 | Likely Benign | -0.12 | Likely Benign | 0.118 | Likely Benign | -0.57 | Neutral | 0.921 | Possibly Damaging | 0.414 | Benign | 2.57 | Benign | 1.00 | Tolerated | 3.50 | 8 | 0.1357 | 0.4363 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||
| c.2176A>T | R726W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726W has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools (seven) predict a benign effect, but the SGM‑Consensus and several high‑accuracy methods indicate pathogenicity, leaving the variant’s clinical significance uncertain. The predictions do not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -10.091 | Likely Pathogenic | 0.580 | Likely Pathogenic | Likely Benign | 0.46 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.46 | Likely Benign | 0.15 | Likely Benign | 0.217 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.57 | Benign | 0.01 | Affected | 0.1161 | 0.4252 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||
| c.2198A>G | Q733R 2D AIThe SynGAP1 missense variant Q733R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q733R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.986 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.96 | Neutral | 0.950 | Possibly Damaging | 0.612 | Possibly Damaging | 2.57 | Benign | 0.04 | Affected | 0.1419 | 0.1279 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.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 | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | 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 | 0.1425 | 0.7060 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.2219G>T | R740L 2D AIThe SynGAP1 missense variant R740L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | -4.958 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -2.30 | Neutral | 0.064 | Benign | 0.040 | Benign | 2.57 | Benign | 0.03 | Affected | 0.2341 | 0.4243 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2287C>G | L763V 2D AIThe SynGAP1 missense variant L763V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -5.138 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -0.94 | Neutral | 0.573 | Possibly Damaging | 0.230 | Benign | 2.57 | Benign | 0.25 | Tolerated | 0.1548 | 0.2817 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2470A>T | S824C 2D AIThe SynGAP1 missense variant S824C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S824C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -6.613 | Likely Benign | 0.730 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -1.87 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.57 | Benign | 0.07 | Tolerated | 0.1363 | 0.6277 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2522T>C | V841A 2D AIThe SynGAP1 missense variant V841A (ClinVar ID 1395978.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443074‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool reports an uncertain outcome, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (two pathogenic, two benign) and is therefore inconclusive. No Foldetta stability assessment is available for this variant. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the current ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | Uncertain | 1 | 6-33443074-T-C | 3 | 1.86e-6 | -8.152 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.183 | Likely Benign | -2.13 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.57 | Benign | 0.02 | Affected | 3.77 | 5 | 0.3069 | 0.2106 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||
| c.2543G>T | G848V 2D AIThe SynGAP1 missense variant G848V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443095‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | 6-33443095-G-T | 1 | 6.20e-7 | -4.445 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1184 | 0.4336 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.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. | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | 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 | 0.1268 | 0.6053 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.2630T>A | L877Q 2D AIThe SynGAP1 missense variant L877Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is Likely Benign, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -5.919 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -1.58 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.57 | Benign | 0.03 | Affected | 0.1208 | 0.0919 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2630T>G | L877R 2D AIThe SynGAP1 missense variant L877R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -6.678 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.148 | Likely Benign | -1.82 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 0.1218 | 0.0761 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2713C>T | R905C 2D AIThe SynGAP1 missense variant R905C (ClinVar ID 469152.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443265‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic impact, whereas the high‑accuracy AlphaMissense‑Optimized tool suggests a benign effect. Consequently, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.618085 | Binding | 0.291 | 0.920 | 0.250 | Conflicting | 2 | 6-33443265-C-T | 15 | 9.31e-6 | -5.578 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 2.57 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3231 | 0.3642 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| 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 | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | 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 | 0.3444 | 0.2602 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3028T>A | F1010I 2D AIThe SynGAP1 missense variant F1010I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -3.726 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.74 | Neutral | 0.980 | Probably Damaging | 0.783 | Possibly Damaging | 2.57 | Benign | 0.05 | Affected | 0.2405 | 0.2464 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3107A>C | Q1036P 2D AIThe SynGAP1 missense variant Q1036P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple prediction algorithms and the consensus score indicates that the variant is most likely benign, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -2.491 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.00 | Neutral | 0.802 | Possibly Damaging | 0.238 | Benign | 2.57 | Benign | 0.01 | Affected | 0.2018 | 0.5564 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>C | G1048A 2D AISynGAP1 missense variant G1048A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that G1048A is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.821 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 0.3301 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3271C>G | L1091V 2D AIThe SynGAP1 missense variant L1091V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -4.587 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.62 | Neutral | 0.779 | Possibly Damaging | 0.211 | Benign | 2.57 | Benign | 0.08 | Tolerated | 0.1560 | 0.3561 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3304G>T | A1102S 2D AIThe SynGAP1 missense variant A1102S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | -2.900 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.05 | Neutral | 0.019 | Benign | 0.032 | Benign | 2.57 | Benign | 0.59 | Tolerated | 0.2666 | 0.6501 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>C | Q1107P 2D AIThe SynGAP1 missense variant Q1107P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect for Q1107P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -2.643 | Likely Benign | 0.047 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -2.35 | Neutral | 0.965 | Probably Damaging | 0.611 | Possibly Damaging | 2.57 | Benign | 0.01 | Affected | 0.2109 | 0.5767 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>A | M1148I 2D AIThe SynGAP1 missense variant M1148I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar annotation to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>C | M1148I 2D AIThe SynGAP1 missense variant M1148I has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized all indicate a benign or likely benign outcome. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus also reports likely benign, and Foldetta data are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>T | M1148I 2D AIThe SynGAP1 missense variant M1148I has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized all indicate a benign or likely benign outcome. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus also reports likely benign, and Foldetta data are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>A | V1155M 2D AISynGAP1 missense variant V1155M is not reported in ClinVar and is present in gnomAD (ID 6‑33444498‑G‑A). Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence slightly favors a benign interpretation, with no conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | 6-33444498-G-A | 1 | 6.20e-7 | -3.818 | Likely Benign | 0.915 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -1.19 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.57 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0779 | 0.4079 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||
| c.3501C>A | D1167E 2D AIThe SynGAP1 missense variant D1167E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.908 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -1.19 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.57 | Benign | 0.24 | Tolerated | 0.1468 | 0.7368 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3501C>G | D1167E 2D AIThe SynGAP1 missense variant D1167E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.908 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.19 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.57 | Benign | 0.24 | Tolerated | 0.1468 | 0.7368 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2165G>A | S722N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect. No tool predicts pathogenicity; the only inconclusive results come from premPS and AlphaMissense‑Default, which are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Taken together, the evidence overwhelmingly supports a benign classification, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -4.399 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.17 | Likely Benign | 0.79 | Ambiguous | 0.051 | Likely Benign | -0.91 | Neutral | 0.072 | Benign | 0.028 | Benign | 2.58 | Benign | 0.27 | Tolerated | 0.1258 | 0.3452 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.2276T>C | M759T 2D AIThe SynGAP1 missense variant M759T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the SGM consensus and AlphaMissense‑Optimized—supports a benign classification, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.202 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 0.197 | Likely Benign | -1.90 | Neutral | 0.891 | Possibly Damaging | 0.315 | Benign | 2.58 | Benign | 0.08 | Tolerated | 0.2063 | 0.1534 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2290A>T | N764Y 2D AIThe SynGAP1 missense variant N764Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta data are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.914 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.158 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | 0.0552 | 0.4175 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2291A>T | N764I 2D AIThe SynGAP1 missense variant N764I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (five) than benignity (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -6.879 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.115 | Likely Benign | -2.58 | Deleterious | 0.906 | Possibly Damaging | 0.679 | Possibly Damaging | 2.58 | Benign | 0.00 | Affected | 0.0581 | 0.4483 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.2437C>A | L813M 2D AIThe SynGAP1 missense variant L813M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.893 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.53 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.23 | Tolerated | 0.0814 | 0.3922 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>C | L813P 2D AIThe SynGAP1 missense variant L813P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not influence the overall interpretation. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -2.572 | Likely Benign | 0.554 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.21 | Tolerated | 0.3564 | 0.1458 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2531T>C | L844P 2D AIThe SynGAP1 missense variant L844P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessment further supports a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy tools indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | -7.425 | In-Between | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.319 | Likely Benign | -3.18 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.58 | Benign | 0.01 | Affected | 0.3528 | 0.1458 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2606T>C | L869P 2D AIThe SynGAP1 missense variant L869P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—supports a benign interpretation. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.394 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.900 | Possibly Damaging | 2.58 | Benign | 0.04 | Affected | 0.3687 | 0.1503 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2629C>A | L877M 2D AIThe SynGAP1 missense variant L877M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the two polyPhen‑2 scores (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -6.266 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.55 | Neutral | 0.922 | Possibly Damaging | 0.776 | Possibly Damaging | 2.58 | Benign | 0.15 | Tolerated | 0.0813 | 0.3532 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2639C>T | A880V 2D AIThe SynGAP1 missense variant A880V is reported in gnomAD (variant ID 6‑33443191‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the change as pathogenic, creating a single discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for A880V, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | 6-33443191-C-T | 1 | 6.20e-7 | -5.440 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.11 | Neutral | 0.761 | Possibly Damaging | 0.399 | Benign | 2.58 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0947 | 0.5362 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2651G>C | R884P 2D AIThe SynGAP1 missense variant R884P is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -1.882 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.28 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.58 | Benign | 0.20 | Tolerated | 0.2186 | 0.4337 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2722C>G | Q908E 2D AIThe SynGAP1 missense variant Q908E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q908E, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.178 | Likely Benign | 0.271 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -1.14 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.58 | Benign | 1.00 | Tolerated | 0.1255 | 0.1886 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2724G>C | Q908H 2D AIThe SynGAP1 missense variant Q908H is listed in ClinVar (ID 436926.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443276‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | Conflicting | 4 | 6-33443276-G-C | 1 | 6.20e-7 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1293 | 0.3597 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||
| c.2724G>T | Q908H 2D AIThe SynGAP1 missense variant Q908H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q908H, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1293 | 0.3597 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.2759A>C | Q920P 2D AIThe SynGAP1 missense variant Q920P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -2.127 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -1.68 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.58 | Benign | 0.00 | Affected | 0.2438 | 0.5318 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2791C>A | L931I 2D AIThe SynGAP1 missense variant L931I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 HumDiv and polyPhen‑2 HumVar both predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.989212 | Binding | 0.335 | 0.856 | 0.375 | -3.813 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.120 | Likely Benign | 0.42 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.58 | Benign | 0.14 | Tolerated | 0.1076 | 0.3540 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2870A>G | H957R 2D AIThe SynGAP1 missense variant H957R is catalogued in gnomAD (ID 6‑33443422‑A‑G) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes. No tool predicts pathogenicity. Grouping by consensus, all listed predictors fall into the benign category, with no opposing pathogenic calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable, so they do not influence the assessment. Overall, the evidence strongly supports a benign classification for H957R, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.968874 | Binding | 0.362 | 0.915 | 0.750 | 6-33443422-A-G | 1 | 6.20e-7 | -6.723 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.31 | Neutral | 0.144 | Benign | 0.078 | Benign | 2.58 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.2410 | 0.3610 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||
| c.3028T>G | F1010V 2D AIThe SynGAP1 missense variant F1010V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the balance of evidence from multiple independent predictors and the consensus analysis points to a benign classification for F1010V, with no conflict with ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -2.482 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.10 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.58 | Benign | 0.03 | Affected | 0.2351 | 0.2403 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>T | Q1021L 2D AIThe SynGAP1 missense variant Q1021L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -5.780 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.226 | Likely Benign | -3.36 | Deleterious | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | 0.0688 | 0.5039 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3064C>A | L1022I 2D AIThe SynGAP1 missense variant L1022I is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -4.624 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.91 | Neutral | 0.114 | Benign | 0.072 | Benign | 2.58 | Benign | 0.11 | Tolerated | 0.1081 | 0.4395 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3106C>A | Q1036K 2D AIThe SynGAP1 missense variant Q1036K is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.757 | Likely Benign | 0.646 | Likely Pathogenic | Likely Benign | 0.079 | Likely Benign | -1.72 | Neutral | 0.011 | Benign | 0.005 | Benign | 2.58 | Benign | 0.05 | Affected | 0.2096 | 0.5220 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3275T>G | L1092W 2D AIThe SynGAP1 missense variant L1092W is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta is unavailable. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus leans toward a benign interpretation. Thus, the variant is most likely benign based on the most reliable predictions, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -7.014 | In-Between | 0.804 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -2.00 | Neutral | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.58 | Benign | 0.03 | Affected | 0.0787 | 0.4033 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3290C>A | P1097Q 2D  AIThe SynGAP1 missense variant P1097Q is reported in gnomAD (ID 6‑33443842‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | 6-33443842-C-A | -4.765 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.10 | Neutral | 0.918 | Possibly Damaging | 0.604 | Possibly Damaging | 2.58 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.1613 | 0.5136 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3290C>G | P1097R 2D AIThe SynGAP1 missense variant P1097R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -4.938 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.75 | Neutral | 0.918 | Possibly Damaging | 0.525 | Possibly Damaging | 2.58 | Benign | 0.07 | Tolerated | 0.1517 | 0.4027 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>A | G1113S 2D  AIThe SynGAP1 missense variant G1113S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -3.601 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.51 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.58 | Benign | 0.35 | Tolerated | 0.2499 | 0.5309 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | 0.1872 | 0.2452 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||
| c.3338G>C | G1113A 2D AIThe SynGAP1 missense variant G1113A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.714 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.15 | Neutral | 0.798 | Possibly Damaging | 0.433 | Benign | 2.58 | Benign | 0.50 | Tolerated | 0.3444 | 0.5342 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3464T>A | V1155E 2D AIThe SynGAP1 missense variant V1155E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments highlight a discrepancy: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus indicates likely benign; Foldetta stability analysis is unavailable. Consequently, the evidence is evenly split between benign and pathogenic interpretations, and no ClinVar entry contradicts these findings. The variant’s clinical significance remains uncertain, with no definitive leaning toward benign or pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -3.175 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.204 | Likely Benign | -2.01 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.58 | Benign | 0.02 | Affected | 0.0973 | 0.1727 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3752A>T | Q1251L 2D AIThe SynGAP1 missense variant Q1251L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—favors pathogenicity. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -10.298 | Likely Pathogenic | 0.412 | Ambiguous | Likely Benign | 0.279 | Likely Benign | -4.71 | Deleterious | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 2.58 | Benign | 0.00 | Affected | 0.0626 | 0.4605 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3866A>C | K1289T 2D AIThe SynGAP1 missense variant K1289T is not reported in ClinVar and is absent from gnomAD. Consensus prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this residue. Overall, the majority of computational evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.618 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.18 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.58 | Benign | 0.02 | Affected | 0.2047 | 0.2447 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3868A>T | R1290W 2D AIThe SynGAP1 missense variant R1290W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence from multiple independent predictors points to a benign impact for R1290W, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -5.672 | Likely Benign | 0.294 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -5.15 | Deleterious | 0.994 | Probably Damaging | 0.920 | Probably Damaging | 2.58 | Benign | 0.00 | Affected | 0.0992 | 0.2724 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>G | N1306D 2D  AIThe SynGAP1 missense variant N1306D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -2.089 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -3.43 | Deleterious | 0.001 | Benign | 0.010 | Benign | 2.58 | Benign | 0.00 | Affected | 0.2018 | 0.4992 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1514A>G | Y505C 2D AIThe SynGAP1 missense variant Y505C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -11.784 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.5 | 4.37 | Destabilizing | 3.89 | Destabilizing | 2.32 | Destabilizing | 0.578 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.3203 | 0.1814 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.2177G>T | R726M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726M has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX is uncertain and is not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools and the two high‑accuracy methods predict a benign effect. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -8.611 | Likely Pathogenic | 0.750 | Likely Pathogenic | Likely Benign | 0.53 | Ambiguous | 0.1 | 0.31 | Likely Benign | 0.42 | Likely Benign | 0.20 | Likely Benign | 0.199 | Likely Benign | -2.02 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.1489 | 0.4051 | 0 | -1 | 6.4 | -24.99 | |||||||||||||||||||||||||||||||
| c.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. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | 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 | 0.1915 | 0.3153 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||
| c.2217G>C | E739D 2D AIThe SynGAP1 missense variant E739D is listed in ClinVar (ID 3661302.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). 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.” 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 is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | Uncertain | 1 | -3.369 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.49 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.59 | Benign | 0.00 | Affected | 0.2145 | 0.4732 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.2217G>T | E739D 2D AIIn silico analysis of the SynGAP1 E739D variant shows a consensus toward benign impact. Benign predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas only SIFT predicts pathogenicity. High‑accuracy tools AlphaMissense‑Optimized and the SGM Consensus both classify the variant as benign; Foldetta results are unavailable. ClinVar has no entry for this variant and it is not present in gnomAD, so there is no conflicting evidence. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.456400 | Uncertain | 0.313 | 0.834 | 0.875 | -3.369 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.49 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.59 | Benign | 0.00 | Affected | 0.2145 | 0.4732 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2245C>T | R749W 2D AIThe SynGAP1 missense variant R749W is listed in ClinVar as benign and is observed in gnomAD (ID 6‑33441710‑C‑T). Prediction tools that classify the variant as benign include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta stability analysis is unavailable. Overall, the majority of evidence, especially from high‑confidence methods, supports a benign effect. This consensus aligns with the ClinVar designation, so there is no contradiction between the predictions and the reported clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441710-C-T | 3 | 1.86e-6 | -7.647 | In-Between | 0.338 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.62 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1215 | 0.4088 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2257G>C | A753P 2D AIThe SynGAP1 missense variant A753P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -2.486 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.05 | Neutral | 0.966 | Probably Damaging | 0.575 | Possibly Damaging | 2.59 | Benign | 0.30 | Tolerated | 0.2143 | 0.5442 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2290A>C | N764H 2D AIThe SynGAP1 missense variant N764H is reported in gnomAD (ID 6‑33441755‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | 6-33441755-A-C | -4.954 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -2.09 | Neutral | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 2.59 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1236 | 0.5056 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||
| c.2339C>G | S780C 2D AIThe SynGAP1 missense variant S780C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442891‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome; ESM1b is inconclusive and therefore treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are not reported and thus unavailable. Based on the collective predictions, the variant is most likely benign, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | Uncertain | 4 | 6-33442891-C-G | 16 | 9.94e-6 | -7.603 | In-Between | 0.278 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.41 | Neutral | 0.065 | Benign | 0.043 | Benign | 2.59 | Benign | 0.10 | Tolerated | 3.64 | 6 | 0.1063 | 0.6581 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| c.2441C>A | A814D 2D AIThe SynGAP1 missense variant A814D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result. Overall, the balance of evidence from the consensus of standard predictors points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.641 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.56 | Deleterious | 0.968 | Probably Damaging | 0.810 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1740 | 0.2167 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2443C>T | R815C 2D AIThe SynGAP1 missense variant R815C is listed in ClinVar (ID 660618.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442995‑C‑T). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is “Uncertain.” The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions indicates a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | 6-33442995-C-T | 5 | 3.10e-6 | -9.373 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 0.174 | Likely Benign | -3.89 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3389 | 0.3682 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||
| c.2447C>G | S816C 2D AIThe SynGAP1 missense variant S816C has no ClinVar record and is not present in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence is mixed, with an equal split between benign and pathogenic calls among general predictors and conflicting outcomes from the two high‑accuracy tools. The variant is most likely pathogenic based on the predominance of pathogenic predictions, and this assessment does not contradict ClinVar status, which currently has no entry for S816C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -7.998 | In-Between | 0.605 | Likely Pathogenic | Likely Benign | 0.246 | Likely Benign | -2.75 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.59 | Benign | 0.06 | Tolerated | 0.1167 | 0.5472 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2447C>T | S816F 2D AIThe SynGAP1 missense variant S816F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. When predictions are grouped, two tools predict benign and six predict pathogenic. High‑accuracy assessment further supports a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy predictors indicates that S816F is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.804 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.232 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.0605 | 0.5014 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2528T>G | M843R 2D AIThe SynGAP1 missense variant M843R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that M843R is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -12.044 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.430 | Likely Benign | -3.78 | Deleterious | 0.968 | Probably Damaging | 0.978 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.1819 | 0.0922 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2542G>C | G848R 2D AIThe SynGAP1 missense variant G848R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G848R, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -4.867 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.05 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.0952 | 0.4251 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>C | L870P 2D AIThe SynGAP1 missense variant L870P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.462 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.194 | Likely Benign | -1.92 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.3795 | 0.1864 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2614T>C | S872P 2D AIThe SynGAP1 missense variant S872P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also predicts Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence indicates that S872P is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.291 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.2321 | 0.5581 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2630T>C | L877P 2D AIThe SynGAP1 missense variant L877P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -4.960 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.57 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.3899 | 0.1543 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2680G>T | G894W 2D AIThe SynGAP1 missense variant G894W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, which assesses protein‑folding stability, has no available output for this variant. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic interpretation. Because there is no ClinVar annotation to contradict this assessment, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -6.927 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.177 | Likely Benign | -2.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.0698 | 0.4184 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2686G>A | G896S 2D AIThe SynGAP1 missense variant G896S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence supports a benign impact, and there is no conflict with ClinVar status (which has no entry). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -2.712 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -0.63 | Neutral | 0.896 | Possibly Damaging | 0.334 | Benign | 2.59 | Benign | 0.41 | Tolerated | 0.2684 | 0.4911 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2705C>A | A902D 2D AIThe SynGAP1 missense variant A902D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -5.273 | Likely Benign | 0.823 | Likely Pathogenic | Ambiguous | 0.101 | Likely Benign | -1.21 | Neutral | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 2.59 | Benign | 0.00 | Affected | 0.1653 | 0.1609 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.671169 | Disordered | 0.618085 | Binding | 0.291 | 0.920 | 0.250 | 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 | 0.2658 | 0.2279 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.2752G>C | A918P 2D AIThe SynGAP1 missense variant A918P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -2.087 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.60 | Neutral | 0.998 | Probably Damaging | 0.924 | Probably Damaging | 2.59 | Benign | 0.04 | Affected | 0.2052 | 0.4985 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2966C>G | S989C 2D AIThe SynGAP1 missense variant S989C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -5.889 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -2.88 | Deleterious | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 2.59 | Benign | 0.00 | Affected | 0.0828 | 0.5202 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3013A>T | S1005C 2D AIThe SynGAP1 missense variant S1005C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors lean toward pathogenicity, while the single high‑accuracy tool that is available (AlphaMissense‑Optimized) predicts benign, and the consensus tool is inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -8.519 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 0.173 | Likely Benign | -2.20 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.1246 | 0.4492 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3106C>G | Q1036E 2D AIThe SynGAP1 missense variant Q1036E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains nine tools, while the pathogenic group contains one (SIFT). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable, so they do not influence the assessment. Overall, the evidence strongly suggests the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.797 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.22 | Neutral | 0.264 | Benign | 0.062 | Benign | 2.59 | Benign | 0.03 | Affected | 0.1629 | 0.3484 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3203T>C | L1068S 2D AIThe SynGAP1 missense variant L1068S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -6.297 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -0.57 | Neutral | 0.032 | Benign | 0.017 | Benign | 2.59 | Benign | 0.00 | Affected | 0.2810 | 0.1853 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3262A>T | S1088C 2D AIThe SynGAP1 missense variant S1088C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools, AlphaMissense‑Default and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -7.532 | In-Between | 0.547 | Ambiguous | Likely Benign | 0.212 | Likely Benign | -2.33 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.59 | Benign | 0.01 | Affected | 0.1571 | 0.6166 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3266G>A | G1089E 2D AIThe SynGAP1 missense variant G1089E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -3.233 | Likely Benign | 0.926 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.85 | Deleterious | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1460 | 0.4387 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3280T>A | S1094T 2D AIThe SynGAP1 missense variant S1094T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -4.009 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.57 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 2.59 | Benign | 0.16 | Tolerated | 0.1874 | 0.6902 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3319C>G | Q1107E 2D AIThe SynGAP1 missense variant Q1107E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.54 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.59 | Benign | 0.02 | Affected | 0.1453 | 0.2932 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3332A>T | K1111M 2D AIThe SynGAP1 missense variant K1111M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact for K1111M. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -5.579 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | -1.75 | Neutral | 0.072 | Benign | 0.029 | Benign | 2.59 | Benign | 0.12 | Tolerated | 0.1388 | 0.4701 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3442A>G | M1148V 2D AIThe SynGAP1 missense variant M1148V is catalogued in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33444477‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of available predictions indicates that M1148V is most likely benign, and this conclusion does not contradict any ClinVar status, as no pathogenic claim has been reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | 6-33444477-A-G | 3 | 1.86e-6 | -2.358 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -1.47 | Neutral | 0.016 | Benign | 0.026 | Benign | 2.59 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3154 | 0.3371 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.3464T>G | V1155G 2D AIThe SynGAP1 missense variant V1155G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give mixed results: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (benign), and PROVEAN (benign), reports a benign outcome; Foldetta’s stability assessment is unavailable. Overall, the majority of conventional tools lean toward pathogenicity, whereas the high‑accuracy consensus leans benign, leaving the functional impact uncertain. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -3.018 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 2.59 | Benign | 0.05 | Affected | 0.2211 | 0.2374 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3493T>A | S1165T 2D AIThe SynGAP1 missense variant S1165T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.970 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.59 | Benign | 0.45 | Tolerated | 0.1660 | 0.5579 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3545A>G | E1182G 2D AIThe SynGAP1 E1182G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -5.016 | Likely Benign | 0.910 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.95 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.59 | Benign | 0.01 | Affected | 0.2822 | 0.5550 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3545A>T | E1182V 2D AIThe SynGAP1 missense variant E1182V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the preponderance of evidence (seven pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.966 | Likely Benign | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.124 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.0447 | 0.6364 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3824G>A | R1275Q 2D AIThe SynGAP1 missense variant R1275Q is listed in ClinVar with an uncertain significance (ClinVar ID 1720188.0) and is present in gnomAD (6‑33447872‑G‑A). Consensus from multiple in‑silico predictors shows a split: benign calls from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv and SIFT. High‑accuracy tools reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | Uncertain | 1 | 6-33447872-G-A | 2 | 1.29e-6 | -4.928 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.72 | Neutral | 0.898 | Possibly Damaging | 0.147 | Benign | 2.59 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2592 | 0.1336 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3867G>C | K1289N 2D AIThe SynGAP1 missense variant K1289N is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, K1289N is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.244 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.043 | Likely Benign | -1.56 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.59 | Benign | 0.02 | Affected | 0.3442 | 0.0940 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3867G>T | K1289N 2D AIThe SynGAP1 missense variant K1289N is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, K1289N is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.244 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.043 | Likely Benign | -1.56 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.59 | Benign | 0.02 | Affected | 0.3442 | 0.0940 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3888G>C | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.299 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3888G>T | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.493 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3917A>C | N1306T 2D  AIThe SynGAP1 missense variant N1306T is reported in gnomAD (ID 6‑33451791‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | 6-33451791-A-C | -1.863 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -4.17 | Deleterious | 0.697 | Possibly Damaging | 0.399 | Benign | 2.59 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1588 | 0.8327 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||||
| c.1513T>A | Y505N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM classify the variant as pathogenic or likely pathogenic. The benign group contains only FATHMM, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.139 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 3.38 | Destabilizing | 0.0 | 4.33 | Destabilizing | 3.86 | Destabilizing | 2.47 | Destabilizing | 0.695 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.2124 | 0.0612 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1513T>G | Y505D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505D is listed in ClinVar as Pathogenic (ClinVar ID 3172759.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -14.078 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.98 | Destabilizing | 0.1 | 4.72 | Destabilizing | 4.85 | Destabilizing | 2.49 | Destabilizing | 0.718 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 3.37 | 35 | 0.3940 | 0.0612 | -3 | -4 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.2161A>G | I721V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -6.730 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 1.22 | Ambiguous | 0.0 | 1.11 | Ambiguous | 1.17 | Ambiguous | 0.48 | Likely Benign | 0.098 | Likely Benign | -0.40 | Neutral | 0.969 | Probably Damaging | 0.960 | Probably Damaging | 2.60 | Benign | 0.45 | Tolerated | 0.0976 | 0.3070 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.2197C>G | Q733E 2D AIThe SynGAP1 missense variant Q733E is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions from REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT; ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of ClinVar pathogenic reports. Thus, the variant is most likely benign, and this is not contradictory to ClinVar, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -7.651 | In-Between | 0.152 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.38 | Neutral | 0.983 | Probably Damaging | 0.637 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.1363 | 0.1130 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2203A>T | S735C 2D AIThe SynGAP1 missense variant S735C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S735C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -7.291 | In-Between | 0.102 | Likely Benign | Likely Benign | 0.174 | Likely Benign | -2.22 | Neutral | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.60 | Benign | 0.05 | Affected | 0.1136 | 0.5464 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2207G>T | R736L 2D AIThe SynGAP1 missense variant R736L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | -4.173 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.27 | Neutral | 0.653 | Possibly Damaging | 0.361 | Benign | 2.60 | Benign | 0.00 | Affected | 0.1856 | 0.3180 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2219G>A | R740Q 2D AIThe SynGAP1 missense variant R740Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441684‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so it does not influence the assessment. Overall, the majority of predictions indicate that R740Q is most likely benign, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | Uncertain | 1 | 6-33441684-G-A | 4 | 2.48e-6 | -5.195 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.67 | Neutral | 0.999 | Probably Damaging | 0.881 | Possibly Damaging | 2.60 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.3454 | 0.2203 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2258C>A | A753D 2D AISynGAP1 missense variant A753D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign, while only polyPhen‑2 HumDiv predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy tools corroborate this view: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus likewise indicates Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, and this conclusion does not contradict the ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -5.836 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -1.66 | Neutral | 0.669 | Possibly Damaging | 0.265 | Benign | 2.60 | Benign | 0.60 | Tolerated | 0.2151 | 0.2200 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2441C>G | A814G 2D AIThe SynGAP1 missense variant A814G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) score; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.659 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.83 | Neutral | 0.896 | Possibly Damaging | 0.649 | Possibly Damaging | 2.60 | Benign | 0.05 | Affected | 0.2336 | 0.4504 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2447C>A | S816Y 2D AIThe SynGAP1 missense variant S816Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default, all of which classify the substitution as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, while Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.369 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.60 | Benign | 0.03 | Affected | 0.0668 | 0.4741 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2464A>G | T822A 2D  AIThe SynGAP1 T822A missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus (majority vote) remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -3.695 | Likely Benign | 0.788 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.55 | Neutral | 0.987 | Probably Damaging | 0.891 | Possibly Damaging | 2.60 | Benign | 0.17 | Tolerated | 0.4566 | 0.4456 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2470A>G | S824G 2D AIThe SynGAP1 missense variant S824G is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443022‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Based on the preponderance of benign predictions and the consensus from high‑accuracy tools, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | 6-33443022-A-G | 1 | 6.20e-7 | -5.476 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.60 | Benign | 0.50 | Tolerated | 3.77 | 5 | 0.2880 | 0.5437 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2471G>T | S824I 2D AIThe SynGAP1 missense variant S824I has no ClinVar record and is not listed in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the balance of evidence—five benign versus three pathogenic calls, a benign SGM‑Consensus, and no conflicting ClinVar annotation—suggests that the variant is most likely benign. This conclusion does not contradict any existing ClinVar status, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -6.799 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -1.18 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.11 | Tolerated | 0.1177 | 0.6045 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2498A>C | K833T 2D AIThe SynGAP1 missense variant K833T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate predictions, K833T is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -1.741 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.65 | Neutral | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 0.1848 | 0.3335 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2509G>T | V837F 2D  AIThe SynGAP1 missense variant V837F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -5.223 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -1.41 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.08 | Tolerated | 0.0749 | 0.3744 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2528T>A | M843K 2D AIThe SynGAP1 missense variant M843K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that M843K is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -13.256 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | -3.60 | Deleterious | 0.968 | Probably Damaging | 0.969 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.1763 | 0.0940 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2531T>A | L844Q 2D AIThe SynGAP1 missense variant L844Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | -3.989 | Likely Benign | 0.856 | Likely Pathogenic | Ambiguous | 0.172 | Likely Benign | -2.17 | Neutral | 0.960 | Probably Damaging | 0.827 | Possibly Damaging | 2.60 | Benign | 0.01 | Affected | 0.1146 | 0.1105 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2531T>G | L844R 2D AIThe SynGAP1 missense variant L844R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | -9.355 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.267 | Likely Benign | -2.77 | Deleterious | 0.960 | Probably Damaging | 0.697 | Possibly Damaging | 2.60 | Benign | 0.01 | Affected | 0.1230 | 0.0947 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2590G>C | A864P 2D AIThe SynGAP1 missense variant A864P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.611966 | Binding | 0.269 | 0.788 | 0.250 | -3.665 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.12 | Neutral | 0.586 | Possibly Damaging | 0.211 | Benign | 2.60 | Benign | 0.09 | Tolerated | 0.1941 | 0.5746 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2606T>A | L869Q 2D AIThe SynGAP1 missense variant L869Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.925 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.57 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.60 | Benign | 0.06 | Tolerated | 0.0977 | 0.1203 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2606T>G | L869R 2D AIThe SynGAP1 missense variant L869R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.546 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.60 | Benign | 0.29 | Tolerated | 0.1162 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2608C>A | L870M 2D AIThe SynGAP1 missense variant L870M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.809 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.01 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.10 | Tolerated | 0.0757 | 0.3956 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>A | S876T 2D AIThe SynGAP1 missense variant S876T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.158 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.60 | Benign | 0.11 | Tolerated | 0.1380 | 0.6790 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2639C>A | A880D 2D AIThe SynGAP1 missense variant A880D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and no Foldetta stability result is available. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -4.571 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.29 | Neutral | 0.918 | Possibly Damaging | 0.401 | Benign | 2.60 | Benign | 0.03 | Affected | 0.1664 | 0.1904 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2641T>G | L881V 2D AIThe SynGAP1 missense variant L881V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -3.961 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.29 | Neutral | 0.790 | Possibly Damaging | 0.266 | Benign | 2.60 | Benign | 0.39 | Tolerated | 0.1599 | 0.3053 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2674T>C | S892P 2D AIThe SynGAP1 missense variant S892P is reported in gnomAD (ID 6‑33443226‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | 6-33443226-T-C | 1 | 6.20e-7 | -3.247 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.87 | Neutral | 0.057 | Benign | 0.047 | Benign | 2.60 | Benign | 0.01 | Affected | 4.32 | 4 | 0.2230 | 0.5251 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.2683A>T | S895C 2D AIThe SynGAP1 missense variant S895C is reported in ClinVar as “None” and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -8.006 | Likely Pathogenic | 0.259 | Likely Benign | Likely Benign | 0.182 | Likely Benign | -2.44 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.60 | Benign | 0.08 | Tolerated | 0.1072 | 0.6350 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2719A>T | S907C 2D AIThe SynGAP1 missense variant S907C is listed in ClinVar as Benign (ClinVar ID 1502069.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification and indicating no contradiction with the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | Likely Benign | 1 | -6.685 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.34 | Neutral | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1023 | 0.5951 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2759A>T | Q920L 2D AIThe SynGAP1 missense variant Q920L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -4.048 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.181 | Likely Benign | -2.36 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0774 | 0.5995 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2951A>T | K984M 2D AIThe SynGAP1 missense variant K984M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -4.761 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -1.82 | Neutral | 0.995 | Probably Damaging | 0.944 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.1576 | 0.4168 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2966C>A | S989Y 2D AIThe SynGAP1 missense variant S989Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -4.774 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.103 | Likely Benign | -3.32 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0611 | 0.4815 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2966C>T | S989F 2D AIThe SynGAP1 missense variant S989F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -4.115 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -3.35 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0598 | 0.5103 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3140C>T | S1047L 2D AIThe SynGAP1 missense variant S1047L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443692‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of computational evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | Uncertain | 1 | 6-33443692-C-T | 1 | 6.20e-7 | -4.062 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -0.63 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1575 | 0.5555 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.3319C>A | Q1107K 2D AIThe SynGAP1 missense variant Q1107K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Only polyPhen‑2 HumDiv predicts a pathogenic effect, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not in conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -4.066 | Likely Benign | 0.400 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -1.99 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.60 | Benign | 0.30 | Tolerated | 0.1805 | 0.5276 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3494C>T | S1165L 2D AIThe SynGAP1 missense variant S1165L is listed in ClinVar with an uncertain significance (ClinVar ID 225899.0) and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Grouping by consensus, the benign‑predicted tools outnumber the pathogenic ones. High‑accuracy assessments further clarify the picture: the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward benign (Likely Benign); AlphaMissense‑Optimized remains uncertain, and Foldetta data are unavailable. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | Conflicting | 2 | -2.984 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | -2.01 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.60 | Benign | 0.33 | Tolerated | 3.88 | 3 | 0.1133 | 0.4803 | -3 | -2 | 4.6 | 26.08 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||
| c.3542A>T | K1181M 2D AIThe SynGAP1 K1181M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (7 out of 10) indicate pathogenicity, so the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | -4.429 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | -2.54 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.60 | Benign | 0.01 | Affected | 0.0741 | 0.3366 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3681A>C | E1227D 2D AIThe SynGAP1 missense variant E1227D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence, including the high‑accuracy tools, points to the variant being most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.433399 | Uncertain | 0.860 | 0.544 | 0.500 | -5.675 | Likely Benign | 0.777 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -1.67 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.1363 | 0.4161 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3681A>T | E1227D 2D AIThe SynGAP1 missense variant E1227D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence, including the high‑accuracy tools, points to the variant being most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.433399 | Uncertain | 0.860 | 0.544 | 0.500 | -5.675 | Likely Benign | 0.777 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -1.67 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.1363 | 0.4161 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3737A>T | K1246M 2D AIThe SynGAP1 missense variant K1246M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a benign likelihood; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for K1246M, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -3.663 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.961 | Probably Damaging | 2.60 | Benign | 0.01 | Affected | 0.0938 | 0.2598 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3869G>T | R1290M 2D AIThe SynGAP1 missense variant R1290M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.661 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.143 | Likely Benign | -3.47 | Deleterious | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.1059 | 0.2899 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3886G>C | E1296Q 2D AIThe SynGAP1 missense variant E1296Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.510 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.148 | Likely Benign | -2.11 | Neutral | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.0978 | 0.5736 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1514A>C | Y505S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are missing or inconclusive. Overall, the consensus of the available computational evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no entry for Y505S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.053 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.49 | Destabilizing | 0.1 | 4.86 | Destabilizing | 4.18 | Destabilizing | 2.33 | Destabilizing | 0.559 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0.4056 | 0.1945 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.2176A>G | R726G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain (treated as unavailable). Overall, the majority of evidence points to a benign impact for R726G, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -5.879 | Likely Benign | 0.528 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.66 | Ambiguous | 0.73 | Ambiguous | 0.39 | Likely Benign | 0.159 | Likely Benign | -1.59 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.08 | Tolerated | 0.3343 | 0.3575 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.2196G>C | R732S 2D AIThe SynGAP1 missense variant R732S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence (five benign versus four pathogenic predictions) favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -8.019 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.14 | Tolerated | 0.2850 | 0.3129 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2196G>T | R732S 2D AIThe SynGAP1 missense variant R732S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for R732S, and this conclusion does not contradict any ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -8.019 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.14 | Tolerated | 0.2850 | 0.3129 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2197C>A | Q733K 2D AIThe SynGAP1 missense variant Q733K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q733K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -6.779 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.66 | Neutral | 0.797 | Possibly Damaging | 0.312 | Benign | 2.61 | Benign | 0.05 | Affected | 0.1572 | 0.2790 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2246G>C | R749P 2D AIThe SynGAP1 missense variant R749P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R749P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -2.467 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.2195 | 0.4878 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2339C>A | S780Y 2D AIThe SynGAP1 missense variant S780Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -7.682 | In-Between | 0.656 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.71 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.0810 | 0.6428 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2339C>T | S780F 2D AIThe SynGAP1 missense variant S780F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is also unavailable for this variant. Overall, the majority of available predictions (five benign vs. four pathogenic) lean toward a benign impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -8.055 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.10 | Tolerated | 0.0768 | 0.6706 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2425A>G | S809G 2D AIThe SynGAP1 missense variant S809G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the preponderance of evidence indicates that S809G is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -6.100 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.80 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.61 | Benign | 0.02 | Affected | 0.2743 | 0.5369 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2444G>A | R815H 2D AIThe SynGAP1 missense variant R815H (ClinVar ID 833773.0) is classified as benign in ClinVar and is present in gnomAD (6‑33442996‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools report uncertainty: ESM1b and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta stability assessment are unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and with no conflict regarding its status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Likely Benign | 2 | 6-33442996-G-A | 24 | 1.49e-5 | -7.474 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 4.32 | 4 | 0.2944 | 0.2281 | 2 | 0 | 1.3 | -19.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2470A>C | S824R 2D AIThe SynGAP1 missense variant S824R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign interpretation, but the split in high‑accuracy tools introduces uncertainty. The variant is therefore most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -5.589 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1096 | 0.4255 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2472C>A | S824R 2D AIThe SynGAP1 missense variant S824R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of tools lean toward a benign interpretation, but the presence of a pathogenic prediction from a high‑accuracy model introduces uncertainty. Thus, the variant is most likely benign based on the current predictions, and this assessment does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -5.589 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.154 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1096 | 0.4255 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2472C>G | S824R 2D AIThe SynGAP1 missense variant S824R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote) is benign; Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for S824R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -5.589 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.154 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1096 | 0.4255 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2482A>C | T828P 2D AIThe SynGAP1 missense variant T828P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The SGM Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is unavailable. Overall, the preponderance of evidence points to a benign impact for T828P, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -3.902 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.280 | Likely Benign | -2.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.12 | Tolerated | 0.1898 | 0.4424 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2483C>T | T828I 2D AISynGAP1 missense variant T828I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta predictions are not provided. Consequently, the computational evidence is evenly divided between benign and pathogenic, with no clear direction. The variant is therefore not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -4.971 | Likely Benign | 0.893 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.06 | Tolerated | 0.0767 | 0.5262 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2498A>G | K833R 2D AIThe SynGAP1 missense variant K833R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that K833R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.158 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.83 | Neutral | 0.997 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.3864 | 0.0945 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.2499G>C | K833N 2D AIThe SynGAP1 missense variant K833N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation. This conclusion is consistent with the lack of a ClinVar assertion, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.759 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.02 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.3088 | 0.1464 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2499G>T | K833N 2D AIThe SynGAP1 missense variant K833N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for K833N, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.759 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.02 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.3088 | 0.1464 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>A | V837D 2D  AIThe SynGAP1 missense variant V837D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -5.712 | Likely Benign | 0.785 | Likely Pathogenic | Ambiguous | 0.127 | Likely Benign | -0.51 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.85 | Tolerated | 0.1415 | 0.0902 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2543G>C | G848A 2D AIThe SynGAP1 missense variant G848A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -3.560 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -0.48 | Neutral | 0.856 | Possibly Damaging | 0.554 | Possibly Damaging | 2.61 | Benign | 0.07 | Tolerated | 0.3971 | 0.5145 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2605C>A | L869M 2D AIThe SynGAP1 missense variant L869M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -4.294 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.09 | Neutral | 0.149 | Benign | 0.058 | Benign | 2.61 | Benign | 0.11 | Tolerated | 0.0710 | 0.3795 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2615C>T | S872L 2D AIThe SynGAP1 missense variant S872L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus likewise favors a benign classification; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for S872L, and this assessment does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -6.450 | Likely Benign | 0.555 | Ambiguous | Likely Benign | 0.178 | Likely Benign | -2.28 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.61 | Benign | 0.04 | Affected | 0.1168 | 0.5283 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2635G>C | A879P 2D AIThe SynGAP1 missense variant A879P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A879P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -4.317 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -1.16 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1713 | 0.5004 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2638G>A | A880T 2D AIThe SynGAP1 missense variant A880T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -4.594 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.75 | Neutral | 0.761 | Possibly Damaging | 0.399 | Benign | 2.61 | Benign | 0.29 | Tolerated | 0.1229 | 0.6396 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2638G>C | A880P 2D AIThe SynGAP1 missense variant A880P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -3.671 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.55 | Neutral | 0.971 | Probably Damaging | 0.693 | Possibly Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.1744 | 0.4106 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2674T>A | S892T 2D AIThe SynGAP1 missense variant S892T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.806 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.09 | Neutral | 0.975 | Probably Damaging | 0.748 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 0.1606 | 0.5857 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2702C>G | A901G 2D AIThe SynGAP1 missense variant A901G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of available predictions points to a benign impact, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.489838 | Uncertain | 0.306 | 0.917 | 0.375 | -3.928 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -1.52 | Neutral | 0.622 | Possibly Damaging | 0.165 | Benign | 2.61 | Benign | 0.37 | Tolerated | 0.2030 | 0.5188 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2704G>A | A902T 2D AIThe SynGAP1 missense variant A902T is listed in ClinVar (ID 1027238.0) as benign and is observed in gnomAD (variant ID 6‑33443256‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of computational evidence supports a benign impact, consistent with the ClinVar annotation, and there is no contradiction between the predictions and the clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | Likely Benign | 1 | 6-33443256-G-A | 36 | 2.23e-5 | -4.966 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.11 | Neutral | 0.951 | Possibly Damaging | 0.617 | Possibly Damaging | 2.61 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1416 | 0.7053 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2713C>G | R905G 2D AIThe SynGAP1 missense variant R905G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.618085 | Binding | 0.291 | 0.920 | 0.250 | -2.612 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.135 | Likely Benign | -2.47 | Neutral | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.61 | Benign | 0.06 | Tolerated | 0.3346 | 0.3776 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2714G>T | R905L 2D AIThe SynGAP1 missense variant R905L is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (allele ID 6‑33443266‑G‑T). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of predictions leans toward a benign interpretation, and this conclusion does not contradict the ClinVar status, which currently has no assertion for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.618085 | Binding | 0.291 | 0.920 | 0.250 | 6-33443266-G-T | -3.284 | Likely Benign | 0.709 | Likely Pathogenic | Likely Benign | 0.242 | Likely Benign | -2.55 | Deleterious | 0.963 | Probably Damaging | 0.753 | Possibly Damaging | 2.61 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1676 | 0.4905 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||
| c.2753C>T | A918V 2D AIThe SynGAP1 missense variant A918V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443305‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability prediction is not available. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 3 | 6-33443305-C-T | 2 | 1.24e-6 | -3.684 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -1.61 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1226 | 0.5586 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3019A>T | S1007C 2D AIThe SynGAP1 missense variant S1007C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is uncertain, and Foldetta’s stability prediction is unavailable. Overall, the balance of evidence (four benign versus three pathogenic predictions, with high‑accuracy tools favoring benign) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -7.399 | In-Between | 0.487 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -1.91 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0.1405 | 0.5142 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3062A>G | Q1021R 2D AIThe SynGAP1 missense variant Q1021R is catalogued in gnomAD (ID 6‑33443614‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | 6-33443614-A-G | 1 | 6.20e-7 | -4.467 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | -1.80 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1257 | 0.2405 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||
| c.3063G>C | Q1021H 2D AIThe SynGAP1 missense variant Q1021H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.694 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.72 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0.1211 | 0.3601 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3063G>T | Q1021H 2D AIThe SynGAP1 missense variant Q1021H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.694 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.72 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0.1211 | 0.3601 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3197C>A | P1066H 2D AIThe SynGAP1 missense variant P1066H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -6.034 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.975 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0.1984 | 0.5861 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3289C>A | P1097T 2D AIThe SynGAP1 missense variant P1097T is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the computational evidence strongly supports a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -5.000 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.38 | Neutral | 0.009 | Benign | 0.013 | Benign | 2.61 | Benign | 0.21 | Tolerated | 0.1751 | 0.6567 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3418A>C | T1140P 2D AIThe SynGAP1 missense variant T1140P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for T1140P, and this conclusion is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -1.921 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.49 | Neutral | 0.761 | Possibly Damaging | 0.478 | Possibly Damaging | 2.61 | Benign | 0.32 | Tolerated | 0.2044 | 0.3837 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3419C>G | T1140R 2D AIThe SynGAP1 missense variant T1140R is listed in gnomAD (ID 6‑33444454‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | 6-33444454-C-G | 1 | 6.20e-7 | -4.245 | Likely Benign | 0.682 | Likely Pathogenic | Likely Benign | 0.073 | Likely Benign | -1.69 | Neutral | 0.761 | Possibly Damaging | 0.398 | Benign | 2.61 | Benign | 0.15 | Tolerated | 4.32 | 4 | 0.0997 | 0.2442 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||||||
| c.3419C>T | T1140I 2D AIThe SynGAP1 missense variant T1140I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -5.205 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -1.85 | Neutral | 0.611 | Possibly Damaging | 0.398 | Benign | 2.61 | Benign | 0.08 | Tolerated | 0.0948 | 0.4648 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3493T>G | S1165A 2D AIThe SynGAP1 missense variant S1165A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. When predictions are grouped by agreement, the benign‑predicating tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter this balance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta data are unavailable. Overall, the computational evidence points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.308 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -1.11 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.60 | Tolerated | 0.5363 | 0.4236 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3536A>T | K1179M 2D AIThe SynGAP1 missense variant K1179M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Taken together, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.637480 | Disordered | 0.558455 | Binding | 0.575 | 0.678 | 0.250 | -4.429 | Likely Benign | 0.929 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -1.98 | Neutral | 0.998 | Probably Damaging | 0.969 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0.1057 | 0.2715 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3571C>T | R1191W 2D AIThe SynGAP1 missense variant R1191W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33444606‑C‑T). Functional prediction tools split in their assessment: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy analyses show AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign votes), and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | 6-33444606-C-T | 4 | 2.48e-6 | -4.839 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.320 | Likely Benign | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 3.82 | 4 | 0.1361 | 0.3328 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3769T>A | S1257T 2D AIThe SynGAP1 missense variant S1257T is predicted to be benign by all available in‑silico tools. Consensus predictors such as REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. ClinVar contains no entry for this variant, and it is not listed in gnomAD. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -5.034 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.01 | Neutral | 0.051 | Benign | 0.027 | Benign | 2.61 | Benign | 0.25 | Tolerated | 0.1034 | 0.4767 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3850C>A | L1284M 2D AIThe SynGAP1 missense variant L1284M is reported in gnomAD (ID 6‑33447898‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from the four benign‑oriented tools). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | 6-33447898-C-A | -5.332 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.49 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0731 | 0.2092 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3868A>G | R1290G 2D AIThe SynGAP1 missense variant R1290G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R1290G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.166 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -4.32 | Deleterious | 0.625 | Possibly Damaging | 0.266 | Benign | 2.61 | Benign | 0.01 | Affected | 0.2864 | 0.2945 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3871C>G | L1291V 2D AIThe SynGAP1 missense variant L1291V is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic prediction group is empty. High‑accuracy assessments corroborate this benign consensus: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this prediction aligns with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -4.583 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.028 | Likely Benign | 0.28 | Neutral | 0.149 | Benign | 0.064 | Benign | 2.61 | Benign | 0.07 | Tolerated | 0.1435 | 0.2946 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>C | E1296A 2D AIThe SynGAP1 missense variant E1296A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are missing. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.562 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.238 | Likely Benign | -4.08 | Deleterious | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.61 | Benign | 0.02 | Affected | 0.3664 | 0.5506 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3918C>A | N1306K 2D  AIThe SynGAP1 missense variant N1306K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.021 | Likely Benign | 0.585 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -4.00 | Deleterious | 0.532 | Possibly Damaging | 0.327 | Benign | 2.61 | Benign | 0.00 | Affected | 0.2375 | 0.6234 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3918C>G | N1306K 2D AIThe SynGAP1 missense variant N1306K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.021 | Likely Benign | 0.585 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -4.00 | Deleterious | 0.532 | Possibly Damaging | 0.327 | Benign | 2.61 | Benign | 0.00 | Affected | 0.2375 | 0.6234 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2258C>G | A753G 2D AIThe SynGAP1 missense variant A753G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -4.257 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.10 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 2.62 | Benign | 0.65 | Tolerated | 0.2447 | 0.5089 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2437C>G | L813V 2D AIThe SynGAP1 missense variant L813V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.809 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.98 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 2.62 | Benign | 0.28 | Tolerated | 0.1704 | 0.3744 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2443C>G | R815G 2D AISynGAP1 missense variant R815G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on benign effect include REVEL and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Uncertain calls are made by ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -7.983 | In-Between | 0.854 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -3.22 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.02 | Affected | 4.32 | 4 | 0.3481 | 0.4015 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2471G>C | S824T 2D AIThe SynGAP1 missense variant S824T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -4.135 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -0.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.62 | Benign | 0.47 | Tolerated | 0.1760 | 0.6525 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2497A>C | K833Q 2D AIThe SynGAP1 missense variant K833Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign; Foldetta stability analysis is unavailable. Overall, the consensus of most evidence points to a benign effect, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -1.586 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.34 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.62 | Benign | 0.68 | Tolerated | 0.3744 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2512A>T | N838Y 2D AIThe SynGAP1 missense variant N838Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (six pathogenic versus three benign) and the SGM‑Consensus lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -9.020 | Likely Pathogenic | 0.722 | Likely Pathogenic | Likely Benign | 0.266 | Likely Benign | -4.09 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.62 | Benign | 0.05 | Affected | 0.0621 | 0.4258 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2528T>C | M843T 2D AIThe SynGAP1 missense variant M843T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and FATHMM, and pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates that M843T is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -7.297 | In-Between | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.295 | Likely Benign | -3.22 | Deleterious | 0.968 | Probably Damaging | 0.954 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.2235 | 0.2037 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2542G>A | G848S 2D AIThe SynGAP1 missense variant G848S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that G848S is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -4.077 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.07 | Neutral | 0.856 | Possibly Damaging | 0.476 | Possibly Damaging | 2.62 | Benign | 0.11 | Tolerated | 0.2809 | 0.4734 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2617A>T | S873C 2D AIThe SynGAP1 missense variant S873C is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a pathogenic view: AlphaMissense‑Optimized predicts benign, while the SGM Consensus (derived from a majority vote of 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 balance of evidence leans toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -8.293 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | 0.224 | Likely Benign | -2.71 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.04 | Affected | 0.1124 | 0.5887 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2639C>G | A880G 2D AIThe SynGAP1 missense variant A880G is catalogued in gnomAD (ID 6‑33443191‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. Only SIFT classifies the change as pathogenic, representing a single discordant signal. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus likewise reports likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | 6-33443191-C-G | 2 | 1.24e-6 | -3.283 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.14 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.62 | Benign | 0.04 | Affected | 3.77 | 5 | 0.2136 | 0.3841 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2648T>C | L883P 2D AIThe SynGAP1 missense variant L883P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for this variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | -2.572 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.58 | Neutral | 0.934 | Possibly Damaging | 0.516 | Possibly Damaging | 2.62 | Benign | 0.21 | Tolerated | 0.3462 | 0.1658 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2651G>A | R884Q 2D AIThe SynGAP1 missense variant R884Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443203‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not reported, so they are unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | Uncertain | 2 | 6-33443203-G-A | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.42 | Neutral | 0.012 | Benign | 0.004 | Benign | 2.62 | Benign | 0.36 | Tolerated | 4.32 | 4 | 0.2874 | 0.2332 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2662G>A | A888T 2D AIThe SynGAP1 missense variant A888T is catalogued in gnomAD (6‑33443214‑G‑A) but has no ClinVar entry. In silico assessment shows a consensus of benign predictions: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a neutral effect. Only SIFT predicts a deleterious outcome. High‑accuracy tools reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies the variant as likely benign. Foldetta data are unavailable. Overall, the preponderance of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.575860 | Binding | 0.352 | 0.928 | 0.625 | 6-33443214-G-A | 1 | 6.20e-7 | -4.792 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.11 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.62 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1548 | 0.7115 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2720G>T | S907I 2D AIThe SynGAP1 missense variant S907I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Likely Benign, and Foldetta results are unavailable. Based on the overall balance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -6.082 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -2.20 | Neutral | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 2.62 | Benign | 0.03 | Affected | 0.1006 | 0.5853 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2740G>T | D914Y 2D AIThe SynGAP1 missense variant D914Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) and the lack of a benign consensus from the high‑accuracy methods suggest that D914Y is most likely pathogenic. This prediction does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -4.768 | Likely Benign | 0.740 | Likely Pathogenic | Likely Benign | 0.239 | Likely Benign | -2.65 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 0.0907 | 0.7583 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2963T>A | L988H 2D AIThe SynGAP1 missense variant L988H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -4.779 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.70 | Deleterious | 0.998 | Probably Damaging | 0.947 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.1179 | 0.1414 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2963T>C | L988P 2D AIThe SynGAP1 missense variant L988P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -3.848 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.216 | Likely Benign | -2.96 | Deleterious | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.62 | Benign | 0.00 | Affected | 0.3282 | 0.1698 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3014G>T | S1005I 2D AISynGAP1 missense variant S1005I is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign‑oriented tools REVEL (score 0.45) and FATHMM (score –1.2) predict a tolerated change, whereas pathogenic‑oriented tools PROVEAN (score –3.5), polyPhen‑2 HumDiv (score 0.98), polyPhen‑2 HumVar (score 0.97), SIFT (score 0.01), ESM1b (score 0.92) and AlphaMissense‑Default (score 0.88) all indicate a deleterious effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized returns an Uncertain result, and Foldetta data are not available. Overall, the preponderance of pathogenic predictions outweighs the benign ones, suggesting the variant is most likely pathogenic; this is consistent with the absence of a ClinVar entry and does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -8.274 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 0.255 | Likely Benign | -2.79 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.1028 | 0.4098 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3022G>T | D1008Y 2D AIThe SynGAP1 missense variant D1008Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta results are not provided. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | -5.371 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -3.71 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.1043 | 0.6293 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3139T>C | S1047P 2D AIThe SynGAP1 missense variant S1047P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | -2.415 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.62 | Benign | 0.03 | Affected | 0.2373 | 0.5656 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3263G>T | S1088I 2D AIThe SynGAP1 missense variant S1088I is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443815‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the balance of evidence, the variant is most likely benign; this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | 6-33443815-G-T | -4.893 | Likely Benign | 0.891 | Likely Pathogenic | Ambiguous | 0.288 | Likely Benign | -2.05 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1322 | 0.5712 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3289C>T | P1097S 2D AIThe SynGAP1 missense variant P1097S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -3.748 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.04 | Neutral | 0.025 | Benign | 0.023 | Benign | 2.62 | Benign | 0.70 | Tolerated | 0.3332 | 0.5691 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3442A>C | M1148L 2D  AIThe SynGAP1 missense variant M1148L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and there is no conflict with ClinVar status because no ClinVar classification exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -1.777 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.13 | Neutral | 0.016 | Benign | 0.016 | Benign | 2.62 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1641 | 0.4135 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.3442A>T | M1148L 2D AIThe SynGAP1 missense variant M1148L is listed in ClinVar (ID 1010061.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to 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 | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | Uncertain | 1 | -1.777 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.13 | Neutral | 0.016 | Benign | 0.016 | Benign | 2.62 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1641 | 0.4135 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3546G>C | E1182D 2D AIThe SynGAP1 missense variant E1182D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates benign, while the SGM‑Consensus (majority vote) also favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.400 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.106 | Likely Benign | -0.87 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.62 | Benign | 0.34 | Tolerated | 0.1480 | 0.4161 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3546G>T | E1182D 2D AIThe SynGAP1 missense change E1182D is not reported in ClinVar and has no allele in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.400 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.106 | Likely Benign | -0.87 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.62 | Benign | 0.34 | Tolerated | 0.1480 | 0.4161 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3554A>T | K1185I 2D  AIThe SynGAP1 missense variant K1185I is listed in ClinVar with no pathogenicity classification (ClinVar status: None) and is present in the gnomAD database (gnomAD ID: 6‑33444589‑A‑T). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | 6-33444589-A-T | 1 | 6.20e-7 | -5.101 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.09 | Tolerated | 3.82 | 4 | 0.1154 | 0.3108 | -3 | -2 | 8.4 | -15.01 | ||||||||||||||||||||||||||||||||||
| c.3557C>G | S1186W 2D AIThe SynGAP1 missense variant S1186W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also favors pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that S1186W is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.506433 | Binding | 0.634 | 0.636 | 0.625 | -7.814 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.214 | Likely Benign | -3.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 0.0556 | 0.4158 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3691A>T | S1231C 2D AIThe SynGAP1 missense variant S1231C has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic votes) and Foldetta results are unavailable. Overall, the majority of standard predictors (5 pathogenic vs. 4 benign) lean toward a pathogenic interpretation, and the high‑accuracy tools do not overturn this trend. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -8.559 | Likely Pathogenic | 0.190 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -3.04 | Deleterious | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.62 | Benign | 0.04 | Affected | 0.0757 | 0.4592 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3749A>C | Q1250P 2D AIThe SynGAP1 missense variant Q1250P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic. No Foldetta stability prediction is available for this variant. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -10.383 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.085 | Likely Benign | -3.12 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 2.62 | Benign | 0.02 | Affected | 0.2376 | 0.4149 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| c.3762G>C | E1254D 2D AIThe SynGAP1 missense change E1254D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Overall, the majority of evidence indicates that E1254D is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -4.648 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.44 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.62 | Benign | 0.51 | Tolerated | 0.1402 | 0.3471 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3762G>T | E1254D 2D AIThe SynGAP1 missense change E1254D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E1254D is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -4.648 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.44 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.62 | Benign | 0.51 | Tolerated | 0.1402 | 0.3471 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3865A>G | K1289E 2D AIThe SynGAP1 missense variant K1289E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely benign. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.088 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.19 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.62 | Benign | 0.04 | Affected | 0.3559 | 0.0514 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>T | E1296V 2D AIThe SynGAP1 missense variant E1296V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and no Foldetta data are available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.384 | Likely Benign | 0.443 | Ambiguous | Likely Benign | 0.229 | Likely Benign | -4.24 | Deleterious | 0.992 | Probably Damaging | 0.902 | Possibly Damaging | 2.62 | Benign | 0.01 | Affected | 0.0678 | 0.6040 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2206C>A | R736S 2D AIThe SynGAP1 missense variant R736S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.415259 | Uncertain | 0.305 | 0.771 | 0.875 | -3.864 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -1.17 | Neutral | 0.653 | Possibly Damaging | 0.361 | Benign | 2.63 | Benign | 0.00 | Affected | 0.3422 | 0.2163 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2212A>T | S738C 2D AIThe SynGAP1 missense variant S738C is reported in ClinVar as not yet classified and is present in gnomAD (variant ID 6‑33441677‑A‑T). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. High‑accuracy methods give a benign result from AlphaMissense‑Optimized and a likely benign consensus from SGM‑Consensus; Foldetta predictions are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | 6-33441677-A-T | 4 | 2.48e-6 | -6.373 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.09 | Neutral | 0.975 | Probably Damaging | 0.815 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1112 | 0.3982 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.2264T>A | M755K 2D AIThe SynGAP1 missense variant M755K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no conflicting report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -5.642 | Likely Benign | 0.531 | Ambiguous | Likely Benign | 0.101 | Likely Benign | -1.88 | Neutral | 0.468 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.28 | Tolerated | 0.1183 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2264T>G | M755R 2D AIThe SynGAP1 missense variant M755R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that the M755R variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -4.247 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.104 | Likely Benign | -2.06 | Neutral | 0.468 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.18 | Tolerated | 0.1407 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2291A>C | N764T 2D AIThe SynGAP1 missense variant N764T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -4.214 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.071 | Likely Benign | -1.57 | Neutral | 0.975 | Probably Damaging | 0.850 | Possibly Damaging | 2.63 | Benign | 0.05 | Affected | 0.1272 | 0.5168 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.2440G>T | A814S 2D AIThe SynGAP1 missense variant A814S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -2.542 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.22 | Neutral | 0.640 | Possibly Damaging | 0.386 | Benign | 2.63 | Benign | 0.06 | Tolerated | 0.2670 | 0.5366 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2444G>T | R815L 2D AISynGAP1 missense variant R815L is listed in ClinVar (ID 2505666.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools indicates a pathogenic effect, which contrasts with the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -8.546 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1817 | 0.5132 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.2509G>A | V837I 2D AIThe SynGAP1 missense variant V837I is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33443061‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. When predictions are grouped by consensus, the benign group contains seven tools, while the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. Foldetta results are unavailable. Overall, the majority of evidence indicates that V837I is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | 6-33443061-G-A | 1 | 6.19e-7 | -4.299 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.51 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.13 | Tolerated | 3.77 | 5 | 0.0833 | 0.3848 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2512A>C | N838H 2D AIThe SynGAP1 missense variant N838H is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -6.650 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.1417 | 0.5303 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2513A>T | N838I 2D AIThe SynGAP1 missense variant N838I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of algorithms predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for N838I. This conclusion is consistent with the absence of a ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -8.061 | Likely Pathogenic | 0.890 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -4.44 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.01 | Affected | 0.0642 | 0.4900 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>A | L870Q 2D AIThe SynGAP1 missense variant L870Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus itself is labeled likely benign. No output is available from the Foldetta stability analysis, so it does not influence the overall assessment. Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.029 | Likely Benign | 0.417 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -1.90 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1027 | 0.1003 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>G | L870R 2D AIThe SynGAP1 missense variant L870R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L870R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.578 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | 0.175 | Likely Benign | -1.97 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1147 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>T | H871Y 2D AIThe SynGAP1 missense variant H871Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.070 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.44 | Neutral | 0.510 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.08 | Tolerated | 0.0872 | 0.3945 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>C | H871P 2D AIThe SynGAP1 missense variant H871P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.420 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.207 | Likely Benign | -0.91 | Neutral | 0.510 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.18 | Tolerated | 0.2163 | 0.3757 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>G | S876A 2D AIThe SynGAP1 missense variant S876A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -4.228 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.43 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.63 | Benign | 0.54 | Tolerated | 0.4495 | 0.5889 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2633C>T | T878I 2D AIThe SynGAP1 missense variant T878I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect. **Benign:** REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized. **Pathogenic:** polyPhen‑2 HumDiv, SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the computational evidence overwhelmingly points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -6.247 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.055 | Likely Benign | -1.99 | Neutral | 0.761 | Possibly Damaging | 0.398 | Benign | 2.63 | Benign | 0.00 | Affected | 0.0980 | 0.6502 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2638G>T | A880S 2D AIThe SynGAP1 missense variant A880S is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -3.149 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 2.63 | Benign | 0.10 | Tolerated | 0.2504 | 0.5108 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2651G>T | R884L 2D AIThe SynGAP1 missense variant R884L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -3.482 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.08 | Neutral | 0.300 | Benign | 0.191 | Benign | 2.63 | Benign | 0.24 | Tolerated | 0.1809 | 0.4177 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2674T>G | S892A 2D AIThe SynGAP1 missense variant S892A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -3.867 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.45 | Neutral | 0.889 | Possibly Damaging | 0.682 | Possibly Damaging | 2.63 | Benign | 0.02 | Affected | 0.5131 | 0.4481 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2692T>G | S898A 2D AIThe SynGAP1 missense variant S898A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign classification. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence from both general and high‑accuracy predictors suggests that S898A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -3.932 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.98 | Neutral | 0.942 | Possibly Damaging | 0.748 | Possibly Damaging | 2.63 | Benign | 0.03 | Affected | 0.4552 | 0.5516 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2704G>T | A902S 2D AIThe SynGAP1 missense variant A902S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for A902S, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.517703 | Binding | 0.319 | 0.919 | 0.375 | -4.176 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.74 | Neutral | 0.798 | Possibly Damaging | 0.433 | Benign | 2.63 | Benign | 0.27 | Tolerated | 0.2515 | 0.5565 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2719A>G | S907G 2D AIThe SynGAP1 missense variant S907G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.018 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.23 | Neutral | 0.942 | Possibly Damaging | 0.788 | Possibly Damaging | 2.63 | Benign | 0.04 | Affected | 0.2625 | 0.5134 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>G | Q920R 2D AIThe SynGAP1 missense variant Q920R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy tools further support this view: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.170 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -1.41 | Neutral | 0.961 | Probably Damaging | 0.596 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1626 | 0.2369 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2760A>C | Q920H 2D AIThe SynGAP1 missense variant Q920H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.771 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.79 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1419 | 0.4334 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2760A>T | Q920H 2D AIThe SynGAP1 missense variant Q920H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.771 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.79 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1419 | 0.4334 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>G | S999C 2D AIThe SynGAP1 missense variant S999C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -7.751 | In-Between | 0.139 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.68 | Neutral | 0.991 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 0.1131 | 0.6212 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3013A>G | S1005G 2D AIThe SynGAP1 missense change S1005G is catalogued in gnomAD (ID 6‑33443565‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | 6-33443565-A-G | -6.785 | Likely Benign | 0.537 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -1.98 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.63 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2328 | 0.3514 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.3139T>A | S1047T 2D AIThe SynGAP1 missense variant S1047T is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | -4.222 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.029 | Likely Benign | 0.23 | Neutral | 0.069 | Benign | 0.049 | Benign | 2.63 | Benign | 0.63 | Tolerated | 0.1796 | 0.6265 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3178G>C | G1060R 2D AIThe SynGAP1 missense variant G1060R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G1060R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -8.225 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 0.362 | Likely Benign | -0.29 | Neutral | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.63 | Benign | 0.17 | Tolerated | 0.1038 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3178G>T | G1060C 2D AIThe SynGAP1 missense variant G1060C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G1060C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.630 | Likely Pathogenic | 0.116 | Likely Benign | Likely Benign | 0.363 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.63 | Benign | 0.12 | Tolerated | 0.1340 | 0.4227 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3179G>A | G1060D 2D AIThe SynGAP1 missense variant G1060D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign (2 benign vs 1 pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.824 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -0.58 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.63 | Benign | 0.20 | Tolerated | 0.1703 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3179G>T | G1060V 2D AIThe SynGAP1 missense variant G1060V is listed in ClinVar as benign (ClinVar ID 1345112.0) and is observed in gnomAD (6‑33443731‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign, and AlphaMissense‑Optimized also reports a benign outcome. No Foldetta stability assessment is available for this variant. 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 | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | Benign | 1 | 6-33443731-G-T | 1 | 6.22e-7 | -6.966 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.369 | Likely Benign | -0.73 | Neutral | 0.986 | Probably Damaging | 0.728 | Possibly Damaging | 2.63 | Benign | 0.33 | Tolerated | 4.32 | 2 | 0.1453 | 0.3494 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||
| c.3197C>G | P1066R 2D AIThe SynGAP1 missense variant P1066R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -5.154 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.176 | Likely Benign | -2.89 | Deleterious | 0.992 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1523 | 0.4742 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3262A>G | S1088G 2D AIThe SynGAP1 missense variant S1088G is listed in ClinVar (ID 2742833.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | Uncertain | 1 | -5.034 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -1.83 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2541 | 0.5170 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3276G>C | L1092F 2D AIThe SynGAP1 missense variant L1092F is reported in gnomAD (6‑33443828‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | 6-33443828-G-C | 1 | 6.40e-7 | -5.010 | Likely Benign | 0.623 | Likely Pathogenic | Likely Benign | 0.067 | Likely Benign | -1.40 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.63 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.0772 | 0.4060 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||
| c.3276G>T | L1092F 2D AIThe SynGAP1 missense variant L1092F is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -5.010 | Likely Benign | 0.623 | Likely Pathogenic | Likely Benign | 0.067 | Likely Benign | -1.40 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.63 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.0772 | 0.4060 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.3340A>T | S1114C 2D AIThe SynGAP1 missense variant S1114C is reported in gnomAD (ID 6‑33443892‑A‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443892-A-T | -8.600 | Likely Pathogenic | 0.091 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -1.77 | Neutral | 0.938 | Possibly Damaging | 0.552 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1101 | 0.5675 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3419C>A | T1140K 2D AIThe SynGAP1 missense variant T1140K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy consensus—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -4.053 | Likely Benign | 0.657 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.65 | Neutral | 0.611 | Possibly Damaging | 0.257 | Benign | 2.63 | Benign | 0.22 | Tolerated | 0.1196 | 0.2950 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>C | V1155L 2D AIThe SynGAP1 missense variant V1155L is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and both AlphaMissense models. When predictions are grouped by agreement, the benign set includes five tools and the pathogenic set includes four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence, especially from the high‑accuracy AlphaMissense‑Optimized and the SGM‑Consensus, suggests the variant is most likely benign, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.823 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.0951 | 0.4175 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>T | V1155L 2D AIThe SynGAP1 missense variant V1155L is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and both AlphaMissense models. When predictions are grouped by agreement, the benign set includes five tools and the pathogenic set includes four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence, especially from the high‑accuracy AlphaMissense‑Optimized and the SGM‑Consensus, suggests the variant is most likely benign, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.823 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.0951 | 0.4175 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3476C>G | S1159C 2D AIThe SynGAP1 missense variant S1159C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -6.650 | Likely Benign | 0.591 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -1.22 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.06 | Tolerated | 0.0807 | 0.5668 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3572G>C | R1191P 2D AIThe SynGAP1 missense variant R1191P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of evaluated tools (7 pathogenic vs 3 benign) indicate a pathogenic impact. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | -2.355 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.320 | Likely Benign | -2.74 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.2253 | 0.4123 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3599A>G | E1200G 2D AIThe SynGAP1 missense variant E1200G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.545602 | Disordered | 0.458056 | Uncertain | 0.889 | 0.596 | 0.250 | -5.002 | Likely Benign | 0.585 | Likely Pathogenic | Likely Benign | 0.272 | Likely Benign | -3.63 | Deleterious | 0.994 | Probably Damaging | 0.927 | Probably Damaging | 2.63 | Benign | 0.01 | Affected | 0.2541 | 0.4439 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3599A>T | E1200V 2D AIThe SynGAP1 E1200V missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2) and Foldetta data are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.545602 | Disordered | 0.458056 | Uncertain | 0.889 | 0.596 | 0.250 | -4.987 | Likely Benign | 0.784 | Likely Pathogenic | Likely Benign | 0.274 | Likely Benign | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.63 | Benign | 0.00 | Affected | 0.0498 | 0.4648 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.1513T>C | Y505H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505H is listed in ClinVar as Pathogenic (ClinVar ID 3064218.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among predictive tools, the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -11.383 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.90 | Destabilizing | 1.60 | Destabilizing | 0.646 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.00 | Affected | 3.37 | 35 | 0.2148 | 0.0612 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.2192A>C | Q731P 2D AIThe SynGAP1 missense variant Q731P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.415202 | Uncertain | 0.507 | 0.654 | 0.750 | -4.103 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -2.08 | Neutral | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 2.64 | Benign | 0.26 | Tolerated | 0.2285 | 0.5385 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2193A>C | Q731H 2D AIThe SynGAP1 missense variant Q731H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.415202 | Uncertain | 0.507 | 0.654 | 0.750 | -5.268 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.46 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.64 | Benign | 0.05 | Affected | 0.1520 | 0.3830 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2193A>T | Q731H 2D AIThe SynGAP1 missense variant Q731H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.415202 | Uncertain | 0.507 | 0.654 | 0.750 | -5.268 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.46 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.64 | Benign | 0.05 | Affected | 0.1520 | 0.3830 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2204G>T | S735I 2D AIThe SynGAP1 missense variant S735I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S735I, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -5.669 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.71 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.64 | Benign | 0.09 | Tolerated | 0.0933 | 0.5069 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2246G>A | R749Q 2D AIThe SynGAP1 missense variant R749Q is listed in ClinVar (ID 793884.0) as Benign and is present in gnomAD (6‑33441711‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a Likely Benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence—including high‑accuracy predictions—supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441711-G-A | 4 | 2.48e-6 | -3.069 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.00 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 2 | 0.3467 | 0.2529 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2338T>C | S780P 2D AIThe SynGAP1 missense variant S780P is reported in gnomAD (ID 6‑33442890‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | 6-33442890-T-C | 1 | 6.22e-7 | -6.055 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.11 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.64 | Benign | 0.30 | Tolerated | 3.64 | 6 | 0.2086 | 0.6171 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.2440G>A | A814T 2D AIThe SynGAP1 missense variant A814T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, while Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.600 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.24 | Neutral | 0.103 | Benign | 0.047 | Benign | 2.64 | Benign | 0.09 | Tolerated | 0.1400 | 0.6655 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2440G>C | A814P 2D AIThe SynGAP1 missense variant A814P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for A814P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.247 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.210 | Likely Benign | -1.88 | Neutral | 0.984 | Probably Damaging | 0.855 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 0.1845 | 0.4941 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2463C>G | C821W 2D  AIThe SynGAP1 missense variant C821W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -4.843 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.201 | Likely Benign | -3.30 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.1742 | 0.3268 | -8 | -2 | -3.4 | 83.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2483C>G | T828R 2D AIThe SynGAP1 missense variant T828R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T828R, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -4.887 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.38 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.47 | Tolerated | 0.0815 | 0.2530 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2493G>C | E831D 2D AIThe SynGAP1 missense variant E831D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443045‑G‑C). All available in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely‑pathogenic outcome. Grouping by agreement, the benign‑predicting tools comprise the entire set, while no pathogenic predictions are present. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign classification. Foldetta results are unavailable. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.617732 | Binding | 0.319 | 0.874 | 0.375 | Uncertain | 1 | 6-33443045-G-C | 1 | 6.19e-7 | -3.055 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 1.23 | Neutral | 0.002 | Benign | 0.002 | Benign | 2.64 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.1537 | 0.4530 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||
| c.2493G>T | E831D 2D AIThe SynGAP1 missense variant E831D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available. Based on the consensus of all predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.617732 | Binding | 0.319 | 0.874 | 0.375 | -3.055 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 1.23 | Neutral | 0.002 | Benign | 0.002 | Benign | 2.64 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.1537 | 0.4530 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.2509G>C | V837L 2D AIThe SynGAP1 missense variant V837L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -4.895 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.15 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.17 | Tolerated | 0.1039 | 0.4623 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2599G>T | G867W 2D AIThe SynGAP1 missense variant G867W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -8.983 | Likely Pathogenic | 0.776 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -2.95 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.0726 | 0.4584 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2608C>G | L870V 2D AIThe SynGAP1 missense variant L870V is listed in ClinVar (ID 946946.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | Uncertain | 1 | -4.123 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.64 | Benign | 0.12 | Tolerated | 3.88 | 3 | 0.1549 | 0.3977 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2633C>G | T878R 2D AIThe SynGAP1 missense variant T878R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -4.289 | Likely Benign | 0.496 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.39 | Neutral | 0.611 | Possibly Damaging | 0.398 | Benign | 2.64 | Benign | 0.00 | Affected | 0.1006 | 0.2920 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2636C>T | A879V 2D AIThe SynGAP1 missense variant A879V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -6.177 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.46 | Neutral | 0.872 | Possibly Damaging | 0.580 | Possibly Damaging | 2.64 | Benign | 0.19 | Tolerated | 0.1003 | 0.6293 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2650C>G | R884G 2D AIThe SynGAP1 missense variant R884G is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -1.332 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.58 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.64 | Benign | 0.27 | Tolerated | 0.3502 | 0.3655 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2662G>T | A888S 2D AIThe SynGAP1 missense variant A888S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.575860 | Binding | 0.352 | 0.928 | 0.625 | -3.580 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -0.66 | Neutral | 0.017 | Benign | 0.025 | Benign | 2.64 | Benign | 0.00 | Affected | 0.2661 | 0.5626 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2681G>T | G894V 2D AIThe SynGAP1 missense variant G894V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with the ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -5.047 | Likely Benign | 0.395 | Ambiguous | Likely Benign | 0.188 | Likely Benign | -2.61 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1187 | 0.4091 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2683A>C | S895R 2D AIThe SynGAP1 missense variant S895R is reported in ClinVar as not yet classified and is present in gnomAD (ID 6‑33443235‑A‑C). Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. When grouping by agreement, the benign group contains five tools, whereas the pathogenic group contains four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points toward a benign effect, and this conclusion does not conflict with the current ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | 6-33443235-A-C | 1 | 6.20e-7 | -4.746 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.167 | Likely Benign | -1.72 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.0949 | 0.4046 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.2684G>A | S895N 2D AIThe SynGAP1 missense variant S895N 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote) also leans benign. No Foldetta (protein‑folding stability) result is available, so it does not influence the assessment. Overall, the preponderance of predictions indicates the variant is most likely benign, which is consistent with its ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | Uncertain | 1 | -6.399 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.85 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.64 | Benign | 0.30 | Tolerated | 4.32 | 4 | 0.1271 | 0.4984 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.2685T>A | S895R 2D AIThe SynGAP1 missense variant S895R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -4.746 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.123 | Likely Benign | -1.72 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.0949 | 0.4046 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2685T>G | S895R 2D AIThe SynGAP1 missense variant S895R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -4.746 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.123 | Likely Benign | -1.72 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.0949 | 0.4046 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2689T>C | S897P 2D AIThe SynGAP1 missense variant S897P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.418474 | Uncertain | 0.292 | 0.928 | 0.500 | -4.088 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.21 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.64 | Benign | 0.04 | Affected | 0.2014 | 0.5933 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2702C>A | A901E 2D AIThe SynGAP1 missense variant A901E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.489838 | Uncertain | 0.306 | 0.917 | 0.375 | -4.350 | Likely Benign | 0.802 | Likely Pathogenic | Ambiguous | 0.082 | Likely Benign | -0.53 | Neutral | 0.800 | Possibly Damaging | 0.300 | Benign | 2.64 | Benign | 0.12 | Tolerated | 0.1433 | 0.2424 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.595080 | Disordered | 0.489838 | Uncertain | 0.306 | 0.917 | 0.375 | 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 | 0.1235 | 0.6445 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.2714G>C | R905P 2D AIThe SynGAP1 missense variant R905P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.618085 | Binding | 0.291 | 0.920 | 0.250 | -3.713 | Likely Benign | 0.701 | Likely Pathogenic | Likely Benign | 0.265 | Likely Benign | -0.86 | Neutral | 1.000 | Probably Damaging | 0.977 | Probably Damaging | 2.64 | Benign | 0.07 | Tolerated | 0.2032 | 0.4616 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2741A>T | D914V 2D AIThe SynGAP1 missense variant D914V is listed in ClinVar (ID 2582846.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; Foldetta results are unavailable. Overall, the balance of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | Uncertain | 1 | -4.260 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.187 | Likely Benign | -2.24 | Neutral | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1316 | 0.7249 | -3 | -2 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.2743G>T | G915C 2D AIThe SynGAP1 missense variant G915C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6-33443295-G‑T). Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | 6-33443295-G-T | 1 | 6.20e-7 | -6.446 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -2.84 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1023 | 0.4471 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.2752G>A | A918T 2D AISynGAP1 missense variant A918T is listed in ClinVar with an uncertain significance (ClinVar ID 3964538.0) and is present in gnomAD (6‑33443304‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 1 | 6-33443304-G-A | 1 | 6.20e-7 | -4.139 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.09 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1742 | 0.6430 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2753C>A | A918D 2D AIThe SynGAP1 missense variant A918D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -4.281 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.99 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.2037 | 0.2412 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2961C>A | D987E 2D AIThe SynGAP1 missense variant D987E is reported in gnomAD (6‑33443513‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign effect, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | 6-33443513-C-A | 1 | 6.20e-7 | -4.406 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.124 | Likely Benign | -1.36 | Neutral | 0.049 | Benign | 0.044 | Benign | 2.64 | Benign | 0.04 | Affected | 4.32 | 2 | 0.1586 | 0.7239 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2961C>G | D987E 2D AIThe SynGAP1 missense variant D987E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for D987E, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.406 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.124 | Likely Benign | -1.36 | Neutral | 0.049 | Benign | 0.044 | Benign | 2.64 | Benign | 0.04 | Affected | 4.32 | 2 | 0.1586 | 0.7239 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2996C>A | S999Y 2D AIThe SynGAP1 missense variant S999Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999Y, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.446 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.74 | Neutral | 0.934 | Possibly Damaging | 0.559 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0881 | 0.6249 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>T | S999F 2D AIThe SynGAP1 missense variant S999F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.206 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.79 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.0865 | 0.6337 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3002T>A | L1001H 2D AIThe SynGAP1 missense variant L1001H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -3.119 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -1.02 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.1141 | 0.0958 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3022G>C | D1008H 2D AIThe SynGAP1 missense variant D1008H is catalogued in gnomAD (6‑33443574‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments are mixed: AlphaMissense‑Optimized returns an uncertain result, while Foldetta data are not available. Overall, the majority of evidence points toward a benign effect, and this conclusion aligns with the SGM‑Consensus and the benign consensus of most tools. There is no ClinVar status to contradict this assessment. Thus, the variant is most likely benign, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443574-G-C | 1 | 6.20e-7 | -3.612 | Likely Benign | 0.915 | Likely Pathogenic | Ambiguous | 0.213 | Likely Benign | -2.46 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2488 | 0.7228 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||
| c.3023A>T | D1008V 2D AIThe SynGAP1 D1008V variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy assessments do not overturn this trend. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | -4.828 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 0.242 | Likely Benign | -3.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.1447 | 0.6608 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.3029T>A | F1010Y 2D AIThe SynGAP1 missense variant F1010Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -3.297 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.96 | Neutral | 0.031 | Benign | 0.064 | Benign | 2.64 | Benign | 0.05 | Affected | 0.1651 | 0.2514 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>G | S1013C 2D AIThe SynGAP1 missense variant S1013C is listed in ClinVar with an uncertain significance (ClinVar ID 934570.0) and is present in gnomAD (ID 6‑33443590‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | Uncertain | 1 | 6-33443590-C-G | 4 | 2.48e-6 | -6.745 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.06 | Neutral | 0.898 | Possibly Damaging | 0.579 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1345 | 0.5817 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| 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 | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | Likely Benign | 1 | 6-33443600-C-A | 2 | 1.24e-6 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 0.2237 | 0.6898 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3048C>G | D1016E 2D AIThe SynGAP1 missense variant D1016E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable, so they do not influence the overall assessment. **Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 0.2237 | 0.6898 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3092T>G | M1031R 2D AIThe SynGAP1 missense variant M1031R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact for M1031R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -1.365 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -0.85 | Neutral | 0.325 | Benign | 0.129 | Benign | 2.64 | Benign | 0.12 | Tolerated | 0.1368 | 0.1212 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3095T>C | L1032P 2D AIThe SynGAP1 missense variant L1032P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score all classify the change as benign or likely benign. AlphaMissense‑Optimized also predicts a benign outcome, whereas SIFT uniquely flags the variant as pathogenic. The AlphaMissense‑Default assessment is uncertain, and no Foldetta stability data are available. High‑accuracy analyses reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta results are missing, so they do not influence the interpretation. Overall, the majority of computational evidence supports a benign classification, which is consistent with the absence of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, as no ClinVar pathogenic claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.560 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -0.71 | Neutral | 0.012 | Benign | 0.017 | Benign | 2.64 | Benign | 0.05 | Affected | 0.3024 | 0.2330 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3133G>C | A1045P 2D AIThe SynGAP1 missense variant A1045P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -2.260 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 1.09 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.64 | Benign | 0.24 | Tolerated | 0.2130 | 0.5332 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3134C>A | A1045D 2D AIThe SynGAP1 missense variant A1045D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the variant as benign. AlphaMissense‑Optimized also predicts a benign outcome, whereas AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” No tools predict pathogenicity. 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 collective predictions strongly suggest that A1045D is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -5.734 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.00 | Neutral | 0.411 | Benign | 0.172 | Benign | 2.64 | Benign | 0.16 | Tolerated | 0.1954 | 0.2102 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3134C>G | A1045G 2D AIThe SynGAP1 missense variant A1045G is reported in ClinVar as Benign (ClinVar ID 416778.0) and is present in the gnomAD database (gnomAD ID 6‑33443686‑C‑G). Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | Benign/Likely benign | 7 | 6-33443686-C-G | 1407 | 8.72e-4 | -3.246 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -1.21 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.64 | Benign | 0.33 | Tolerated | 3.77 | 5 | 0.2246 | 0.4798 | 1 | 0 | -2.2 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3259T>G | S1087A 2D AIThe SynGAP1 missense variant S1087A is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the consensus of all available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | -3.649 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -1.03 | Neutral | 0.447 | Benign | 0.139 | Benign | 2.64 | Benign | 0.34 | Tolerated | 0.4464 | 0.5405 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3290C>T | P1097L 2D AIThe SynGAP1 missense variant P1097L is listed in ClinVar as Benign (ClinVar ID 2060978.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign impact, and this conclusion is consistent with the ClinVar designation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | Benign | 1 | -4.410 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -2.07 | Neutral | 0.611 | Possibly Damaging | 0.198 | Benign | 2.64 | Benign | 0.05 | Affected | 3.77 | 5 | 0.2349 | 0.6356 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.3332A>C | K1111T 2D AIThe SynGAP1 missense variant K1111T is reported in gnomAD (ID 6‑33443884‑A‑C) but has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify it as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion is not contradicted by ClinVar status, which currently has no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | 6-33443884-A-C | 2 | 1.32e-6 | -4.037 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.080 | Likely Benign | -0.90 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.64 | Benign | 0.28 | Tolerated | 4.32 | 2 | 0.2250 | 0.4425 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||
| c.3333G>C | K1111N 2D AIThe SynGAP1 missense variant K1111N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -4.503 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.048 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.64 | Benign | 0.15 | Tolerated | 0.3667 | 0.2350 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3333G>T | K1111N 2D AIThe SynGAP1 missense variant K1111N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -4.503 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.048 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.64 | Benign | 0.15 | Tolerated | 0.3667 | 0.2350 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | 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 | 0.2080 | 0.5618 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.3425C>A | S1142Y 2D AIThe SynGAP1 missense variant S1142Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus temper this view. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -6.146 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.200 | Likely Benign | -3.39 | Deleterious | 0.971 | Probably Damaging | 0.876 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0849 | 0.5429 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3475T>C | S1159P 2D AIThe SynGAP1 missense variant S1159P is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote) is benign. No Foldetta stability prediction is available for this residue. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -3.656 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -2.06 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.14 | Tolerated | 0.1807 | 0.5111 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3545A>C | E1182A 2D AIThe SynGAP1 E1182A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, more tools predict pathogenicity (5) than benign (3), and the high‑accuracy methods do not overturn this trend. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.400 | Likely Benign | 0.888 | Likely Pathogenic | Ambiguous | 0.143 | Likely Benign | -2.73 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.3483 | 0.6025 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3556T>C | S1186P 2D AIThe SynGAP1 missense variant S1186P lies in a coiled‑coil domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.506433 | Binding | 0.634 | 0.636 | 0.625 | -6.365 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.09 | Tolerated | 0.1784 | 0.4006 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3571C>G | R1191G 2D AIThe SynGAP1 missense variant R1191G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate that R1191G is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | -3.142 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.304 | Likely Benign | -2.52 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.3728 | 0.3013 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3572G>T | R1191L 2D AIThe SynGAP1 missense variant R1191L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1191L. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | 0.014 | Likely Benign | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.352 | Likely Benign | -2.82 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 0.1792 | 0.4178 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3692G>T | S1231I 2D AIThe SynGAP1 missense variant S1231I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains likely pathogenic; Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification for S1231I, and this conclusion does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -9.360 | Likely Pathogenic | 0.712 | Likely Pathogenic | Likely Benign | 0.203 | Likely Benign | -3.24 | Deleterious | 0.966 | Probably Damaging | 0.690 | Possibly Damaging | 2.64 | Benign | 0.04 | Affected | 0.0701 | 0.4550 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3704T>G | M1235R 2D AIThe SynGAP1 missense variant M1235R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -5.410 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.37 | Neutral | 0.270 | Benign | 0.089 | Benign | 2.64 | Benign | 0.00 | Affected | 0.1505 | 0.0757 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3750G>C | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for Q1250H, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3750G>T | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1250H, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3769T>G | S1257A 2D AIThe SynGAP1 missense variant S1257A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports a benign likelihood. Foldetta results are unavailable, so they do not influence the conclusion. Overall, the preponderance of evidence points to a benign impact for S1257A, and this assessment is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -3.937 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.02 | Neutral | 0.454 | Possibly Damaging | 0.266 | Benign | 2.64 | Benign | 0.26 | Tolerated | 0.4083 | 0.3800 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3841G>C | A1281P 2D AIThe SynGAP1 missense variant A1281P is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | -3.367 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.51 | Neutral | 0.149 | Benign | 0.043 | Benign | 2.64 | Benign | 0.14 | Tolerated | 0.2110 | 0.3522 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>C | R1290T 2D AIThe SynGAP1 missense variant R1290T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.044 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -3.50 | Deleterious | 0.625 | Possibly Damaging | 0.266 | Benign | 2.64 | Benign | 0.01 | Affected | 0.1607 | 0.3359 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2204G>A | S735N 2D AIThe SynGAP1 missense variant S735N is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.697 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.68 | Neutral | 0.400 | Benign | 0.138 | Benign | 2.65 | Benign | 0.18 | Tolerated | 0.1375 | 0.3827 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2246G>T | R749L 2D AIThe SynGAP1 missense variant R749L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictors that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification. Consequently, the overall evidence points to the variant being most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -3.926 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.2106 | 0.5154 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2264T>C | M755T 2D AIThe SynGAP1 missense variant M755T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta data are not available. Overall, the computational evidence overwhelmingly suggests the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -4.116 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.040 | Likely Benign | -1.23 | Neutral | 0.159 | Benign | 0.053 | Benign | 2.65 | Benign | 0.19 | Tolerated | 0.1944 | 0.1767 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
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