Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | PSMutPred | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | ||||||||||||||||||||||||||||||||||||||
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| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | IP RF | SP RF | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.275G>C | G92A 2D  AIThe SynGAP1 missense variant G92A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns “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 G92A, 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 | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | -4.044 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.080 | Likely Benign | 0.3922 | 0.4930 | -1.53 | Neutral | 0.996 | Probably Damaging | 0.910 | Probably Damaging | 4.08 | Benign | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.326G>T | S109I 2D  AIThe SynGAP1 missense variant S109I is not 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, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta data are unavailable. Overall, the majority of evidence (five benign vs. three pathogenic predictions) points toward a benign impact. This conclusion does not contradict ClinVar, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -5.195 | Likely Benign | 0.927 | Likely Pathogenic | Ambiguous | 0.200 | Likely Benign | 0.0910 | 0.4930 | -2.56 | Deleterious | 0.267 | Benign | 0.039 | Benign | 3.47 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.2295 | 0.4930 | -1.87 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.55 | Benign | 0.23 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3923G>T | R1308L 2D  AIThe SynGAP1 missense variant R1308L is not 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 votes). 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. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | -1.838 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.360 | Likely Benign | 0.1751 | 0.4930 | -4.04 | Deleterious | 0.982 | Probably Damaging | 0.982 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.2777C>A | S926Y 2D  AIThe SynGAP1 missense variant S926Y 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 and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. Overall, the preponderance of evidence points to a pathogenic effect for S926Y, 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.602 | Likely Benign | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.444 | Likely Benign | 0.0602 | 0.4932 | -4.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.2864C>A | S955Y 2D AIThe SynGAP1 missense variant S955Y is 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) 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 | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -6.212 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.1321 | 0.4932 | -1.62 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.2867C>A | S956Y 2D AIThe SynGAP1 missense variant S956Y 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), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -4.920 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.085 | Likely Benign | 0.1449 | 0.4932 | -0.90 | Neutral | 0.411 | Benign | 0.097 | Benign | 1.93 | Pathogenic | 0.22 | Tolerated | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.718G>T | D240Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D240Y missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Taken together, the overwhelming majority of reliable predictors indicate a pathogenic effect for D240Y. This conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -16.890 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.899 | Likely Pathogenic | 0.0439 | 0.4932 | 0.29 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.68 | Ambiguous | -0.01 | Likely Benign | -7.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.1421A>G | D474G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D474G is not reported in ClinVar and is present in gnomAD (ID 6‑33438453‑A‑G). Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta remains uncertain. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | 6-33438453-A-G | 1 | 6.20e-7 | -11.215 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.823 | Likely Pathogenic | 0.3245 | 0.4933 | -0.38 | Likely Benign | 0.0 | 0.82 | Ambiguous | 0.22 | Likely Benign | 0.44 | Likely Benign | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | -1 | 1 | 3.1 | -58.04 | ||||||||||||||||||||
| c.2827G>C | G943R 2D  AIThe SynGAP1 missense variant G943R is reported in gnomAD (variant ID 6-33443379‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity; only ESM1b is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443379-G-C | 1 | 6.20e-7 | -7.159 | In-Between | 0.335 | Likely Benign | Likely Benign | 0.308 | Likely Benign | 0.0976 | 0.4933 | 1.00 | Neutral | 0.411 | Benign | 0.062 | Benign | 2.86 | Benign | 0.94 | Tolerated | 4.32 | 4 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.2842G>C | G948R 2D AIThe SynGAP1 missense variant G948R 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, 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 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -6.782 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.266 | Likely Benign | 0.1069 | 0.4933 | -0.60 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.58 | Benign | 0.04 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2854G>C | G952R 2D AIThe SynGAP1 missense variant G952R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G952R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.974 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.139 | Likely Benign | 0.1145 | 0.4933 | -0.93 | Neutral | 0.077 | Benign | 0.011 | Benign | 3.20 | Benign | 0.02 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3380G>C | G1127A 2D AIThe SynGAP1 missense variant G1127A is listed in ClinVar (ID 426748.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443932‑G‑C). Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the evidence strongly supports a benign classification, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Conflicting | 4 | 6-33443932-G-C | 4 | 2.68e-6 | -5.949 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.164 | Likely Benign | 0.3420 | 0.4933 | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.83 | Benign | 1.00 | Tolerated | 4.32 | 4 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||
| c.1097C>A | T366N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change T366N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as benign. Taken together, the majority of evidence supports a benign impact and is consistent with the absence of any ClinVar pathogenic annotation. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -5.694 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.038 | Likely Benign | 0.1595 | 0.4934 | 0.06 | Likely Benign | 0.0 | 0.36 | Likely Benign | 0.21 | Likely Benign | 0.92 | Ambiguous | -1.72 | Neutral | 0.454 | Possibly Damaging | 0.038 | Benign | 1.72 | Pathogenic | 0.34 | Tolerated | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||
| c.2555G>C | G852A 2D AIThe SynGAP1 missense variant G852A is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -4.493 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.142 | Likely Benign | 0.3895 | 0.4934 | -0.35 | Neutral | 0.393 | Benign | 0.321 | Benign | 4.25 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3949G>A | G1317S 2D  AIThe SynGAP1 missense variant G1317S is listed in ClinVar with an uncertain significance and is present in the gnomAD database. 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 score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence overwhelmingly points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | Conflicting | 3 | 6-33451823-G-A | 1 | 6.26e-7 | -3.522 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.2546 | 0.4935 | -2.45 | Neutral | 0.127 | Benign | 0.045 | Benign | 4.08 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||
| 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 | 0.0676 | 0.4936 | -3.08 | Deleterious | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||
| c.260C>T | S87F 2D  AIThe SynGAP1 missense variant S87F is not 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, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (six out of nine) indicate a pathogenic impact, whereas three predict benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.550904 | Binding | 0.302 | 0.878 | 0.500 | -9.673 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.054 | Likely Benign | 0.0493 | 0.4937 | -2.34 | Neutral | 0.676 | Possibly Damaging | 0.485 | Possibly Damaging | 3.74 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.3014G>C | S1005T 2D  AIThe SynGAP1 missense variant S1005T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -6.015 | Likely Benign | 0.454 | Ambiguous | Likely Benign | 0.120 | Likely Benign | 0.1600 | 0.4937 | -1.30 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1054A>G | T352A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, integrating FoldX‑MD (benign) and Rosetta (uncertain), reports benign stability. Overall, the preponderance of evidence indicates that T352A is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.952 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.032 | Likely Benign | 0.4341 | 0.4938 | 0.12 | Likely Benign | 0.0 | 0.50 | Ambiguous | 0.31 | Likely Benign | 0.45 | Likely Benign | -1.09 | Neutral | 0.031 | Benign | 0.024 | Benign | 1.73 | Pathogenic | 0.29 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.2020A>T | T674S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.320 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.3329 | 0.4938 | -0.23 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.11 | Likely Benign | -0.14 | Likely Benign | 0.47 | Neutral | 0.107 | Benign | 0.033 | Benign | 3.47 | Benign | 1.00 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.2021C>G | T674S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. With all available evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -5.320 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.3329 | 0.4938 | -0.23 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.11 | Likely Benign | -0.14 | Likely Benign | 0.47 | Neutral | 0.107 | Benign | 0.033 | Benign | 3.47 | Benign | 1.00 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1175A>T | K392M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K392M 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, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy methods give no definitive signal: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable, and Foldetta is uncertain. Overall, the majority of available predictions (six pathogenic vs. three benign) lean toward a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.541878 | Disordered | 0.405672 | Uncertain | 0.319 | 0.702 | 0.750 | -3.856 | Likely Benign | 0.788 | Likely Pathogenic | Ambiguous | 0.665 | Likely Pathogenic | 0.1799 | 0.4941 | 0.52 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.60 | Ambiguous | -0.09 | Likely Benign | -3.24 | Deleterious | 0.952 | Possibly Damaging | 0.496 | Possibly Damaging | 4.59 | Benign | 0.00 | Affected | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||
| 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 | 0.1845 | 0.4941 | -1.88 | Neutral | 0.984 | Probably Damaging | 0.855 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.2771C>T | P924L 2D  AIThe SynGAP1 missense variant P924L is not 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 P924L 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 | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -6.361 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.422 | Likely Benign | 0.1771 | 0.4941 | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.2965T>C | S989P 2D AIThe SynGAP1 missense variant S989P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -2.688 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.1690 | 0.4941 | -2.48 | Neutral | 0.010 | Benign | 0.015 | Benign | 2.67 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.1472C>T | T491I 2D  AIThe SynGAP1 missense variant T491I is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact, while FoldX is uncertain and therefore not counted in either group. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized reports a pathogenic change, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -12.525 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.915 | Likely Pathogenic | 0.0898 | 0.4942 | 1.48 | Ambiguous | 1.8 | 3.73 | Destabilizing | 2.61 | Destabilizing | 0.49 | Likely Benign | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| 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 | 0.2904 | 0.4942 | -3.36 | Deleterious | 0.770 | Possibly Damaging | 0.327 | Benign | 2.45 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||
| c.2864C>T | S955F 2D AISynGAP1 missense variant S955F is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33443416‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions favor a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | Conflicting | 4 | 6-33443416-C-T | 95 | 5.89e-5 | -7.374 | In-Between | 0.176 | Likely Benign | Likely Benign | 0.093 | Likely Benign | 0.1246 | 0.4943 | -1.73 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.2867C>T | S956F 2D AIThe SynGAP1 missense variant S956F is not 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 not available. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any 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 | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -6.654 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.1315 | 0.4943 | -1.04 | Neutral | 0.832 | Possibly Damaging | 0.398 | Benign | 1.93 | Pathogenic | 0.39 | Tolerated | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.893C>A | P298H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P298H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Remaining tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -9.777 | Likely Pathogenic | 0.443 | Ambiguous | Likely Benign | 0.313 | Likely Benign | 0.1769 | 0.4943 | 1.57 | Ambiguous | 0.2 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.83 | Ambiguous | -2.37 | Neutral | 0.999 | Probably Damaging | 0.964 | Probably Damaging | 1.92 | Pathogenic | 0.04 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||
| c.2557G>T | G853C 2D  AIThe SynGAP1 G853C missense variant has no ClinVar record and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from 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 “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.496246 | Uncertain | 0.284 | 0.815 | 0.625 | -7.021 | In-Between | 0.096 | Likely Benign | Likely Benign | 0.120 | Likely Benign | 0.1292 | 0.4944 | -1.65 | Neutral | 0.992 | Probably Damaging | 0.873 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| c.3152G>C | G1051A 2D AIThe SynGAP1 missense variant G1051A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -6.406 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.406 | Likely Benign | 0.3353 | 0.4944 | -0.14 | Neutral | 0.009 | Benign | 0.004 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.3295 | 0.4944 | -0.17 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 2 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||
| c.3179G>C | G1060A 2D AIThe SynGAP1 missense variant G1060A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -6.539 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.341 | Likely Benign | 0.3335 | 0.4944 | 0.30 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.69 | Benign | 0.98 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3347G>C | G1116A 2D AIThe SynGAP1 missense variant G1116A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -5.753 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.288 | Likely Benign | 0.3417 | 0.4944 | -0.24 | Neutral | 0.010 | Benign | 0.022 | Benign | 4.08 | Benign | 0.24 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3350G>C | G1117A 2D AIThe SynGAP1 missense variant G1117A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -6.514 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.183 | Likely Benign | 0.3545 | 0.4944 | -0.41 | Neutral | 0.152 | Benign | 0.071 | Benign | 4.61 | Benign | 0.23 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3359G>C | G1120A 2D AIThe SynGAP1 missense variant G1120A is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; ESM1b is 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 a benign likelihood. Foldetta results are unavailable. Overall, the consensus of available predictions indicates that G1120A is most likely benign, and this conclusion 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 | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -7.192 | In-Between | 0.082 | Likely Benign | Likely Benign | 0.243 | Likely Benign | 0.3435 | 0.4944 | -0.39 | Neutral | 0.264 | Benign | 0.139 | Benign | 3.64 | Benign | 0.28 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3365G>C | G1122A 2D AIThe SynGAP1 missense variant G1122A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no conflict with ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -6.692 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.168 | Likely Benign | 0.3487 | 0.4944 | -0.52 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.52 | Benign | 0.62 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3368G>C | G1123A 2D AIThe SynGAP1 missense variant G1123A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated methods. High‑accuracy tools confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -6.720 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.240 | Likely Benign | 0.3544 | 0.4944 | -0.55 | Neutral | 0.264 | Benign | 0.103 | Benign | 4.38 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2614T>G | S872A 2D  AIThe SynGAP1 missense variant S872A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign prediction: 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 for S872A, 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 | -4.574 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.5351 | 0.4945 | Weaken | -0.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.77 | Benign | 0.28 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.1574A>T | E525V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E525V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome; FoldX and Rosetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for E525V, 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 | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -13.622 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.683 | Likely Pathogenic | 0.0721 | 0.4946 | 1.10 | Ambiguous | 0.7 | -0.69 | Ambiguous | 0.21 | Likely Benign | 0.00 | Likely Benign | -6.96 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.2293A>G | S765G 2D  AIThe SynGAP1 missense variant S765G 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 result is available, so it does not influence the assessment. Overall, the majority 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 | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -4.658 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.048 | Likely Benign | 0.2894 | 0.4946 | -0.98 | Neutral | 0.963 | Probably Damaging | 0.950 | Probably Damaging | 4.09 | Benign | 0.05 | Affected | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.1559C>G | S520C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520C is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default; Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -6.947 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.720 | Likely Pathogenic | 0.1029 | 0.4948 | 0.05 | Likely Benign | 0.2 | 0.76 | Ambiguous | 0.41 | Likely Benign | 0.53 | Ambiguous | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.2813G>C | G938A 2D AIThe SynGAP1 missense variant G938A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta’s protein‑folding stability analysis is not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.068 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.3462 | 0.4948 | -0.41 | Neutral | 0.979 | Probably Damaging | 0.821 | Possibly Damaging | 2.80 | Benign | 0.82 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3155G>C | G1052A 2D AIThe SynGAP1 missense variant G1052A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -6.945 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.382 | Likely Benign | 0.3259 | 0.4949 | -0.14 | Neutral | 0.649 | Possibly Damaging | 0.287 | Benign | 3.93 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.719A>T | D240V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D240V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score—classify the change as pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D240V. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -15.095 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 0.0610 | 0.4949 | 1.32 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.11 | Likely Benign | -7.94 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 5.82 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.898T>G | S300A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign (3 benign vs. 1 pathogenic). Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -5.420 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.031 | Likely Benign | 0.5135 | 0.4949 | Weaken | 0.08 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.58 | Ambiguous | 0.08 | Likely Benign | -1.18 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.56 | Pathogenic | 0.20 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||
| c.1415A>G | E472G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic or likely pathogenic. Only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, 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. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.239 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.744 | Likely Pathogenic | 0.3343 | 0.4950 | 3.06 | Destabilizing | 0.2 | 2.86 | Destabilizing | 2.96 | Destabilizing | 0.24 | Likely Benign | -6.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1042G>C | V348L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1088 | 0.4953 | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1042G>T | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1088 | 0.4953 | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1280A>T | H427L 2D  3DClick to see structure in 3D Viewer AISynGAP1 H427L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: nine tools (REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while five tools (SGM‑Consensus, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy methods provide a more focused view: AlphaMissense‑Optimized indicates a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, remains pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Taken together, the majority of evidence supports a benign impact for H427L, 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 | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -9.691 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 0.272 | Likely Benign | 0.0942 | 0.4953 | -0.17 | Likely Benign | 0.0 | 0.05 | Likely Benign | -0.06 | Likely Benign | 0.31 | Likely Benign | -5.38 | Deleterious | 0.299 | Benign | 0.033 | Benign | 3.42 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.1288A>G | M430V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated changes. Only polyPhen‑2 HumDiv flags it as pathogenic, while the SGM‑Consensus score is Likely Benign. Stability‑based methods are inconclusive: FoldX and premPS return Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -3.555 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.3397 | 0.4953 | 1.48 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.63 | Ambiguous | 0.87 | Ambiguous | -1.35 | Neutral | 0.918 | Possibly Damaging | 0.185 | Benign | 3.53 | Benign | 0.51 | Tolerated | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||
| c.4004G>C | G1335A 2D AIThe SynGAP1 missense variant G1335A is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for G1335A, 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 | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.942 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.357 | Likely Benign | 0.3383 | 0.4953 | -3.69 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1798C>A | P600T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, Rosetta, and premPS. Those that predict pathogenicity are REVEL, 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, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, while Foldetta indicates a benign effect on protein folding stability. Overall, the majority of computational evidence supports a pathogenic effect for P600T, 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 | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -11.945 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.737 | Likely Pathogenic | 0.1871 | 0.4954 | 2.61 | Destabilizing | 0.1 | -2.90 | Stabilizing | -0.15 | Likely Benign | 0.24 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.34 | Pathogenic | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.580G>C | E194Q 2D  AIThe SynGAP1 missense variant E194Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, more evidence supports a pathogenic classification (5 pathogenic vs. 3 benign predictions). Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -8.902 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | 0.1043 | 0.4954 | -1.97 | Neutral | 0.849 | Possibly Damaging | 0.478 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| c.1343C>T | A448V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448V is not 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 a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools (Rosetta and premPS) yield uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that A448V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -10.372 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.487 | Likely Benign | 0.0950 | 0.4955 | 3.31 | Destabilizing | 0.2 | 1.80 | Ambiguous | 2.56 | Destabilizing | 0.66 | Ambiguous | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.26 | Benign | 0.02 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.140G>C | R47P 2D  AIThe SynGAP1 missense variant R47P is not 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 SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant and is likewise unavailable. High‑accuracy tools specifically indicate a benign prediction from AlphaMissense‑Optimized, while the other high‑accuracy methods (SGM Consensus, Foldetta) provide no definitive assessment. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests 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. | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | -10.316 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 0.195 | Likely Benign | 0.2050 | 0.4956 | -1.63 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 4.02 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1325 | 0.4956 | -1.64 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.50 | Benign | 0.06 | Tolerated | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| c.3461C>T | T1154I 2D AIThe SynGAP1 missense variant T1154I is not reported in ClinVar and has no gnomAD entry. 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 AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also 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 majority of evidence points to a pathogenic impact, 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 | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -4.489 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.351 | Likely Benign | 0.0927 | 0.4956 | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.2828G>C | G943A 2D AIThe SynGAP1 missense variant G943A is reported in gnomAD (ID 6‑33443380‑G‑C) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar pathogenicity, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443380-G-C | 3 | 1.86e-6 | -6.684 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.274 | Likely Benign | 0.3415 | 0.4957 | 0.10 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.87 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.2831G>C | G944A 2D AIThe SynGAP1 missense variant G944A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.397 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.314 | Likely Benign | 0.3352 | 0.4957 | -0.61 | Neutral | 0.059 | Benign | 0.042 | Benign | 3.81 | Benign | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2837G>C | G946A 2D AIThe SynGAP1 missense variant G946A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G946A, 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.004 | In-Between | 0.079 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.3378 | 0.4957 | 0.33 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 4.77 | Benign | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2840G>C | G947A 2D AIThe SynGAP1 missense variant G947A is listed in ClinVar (ID 1595137.0) as Benign and is present in gnomAD (6‑33443392‑G‑C). Prediction tools that assess sequence conservation and functional impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) all classify the variant as Benign. The AlphaMissense suite likewise reports Benign for both its Default and Optimized models. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign. No tool in the dataset predicts pathogenicity. High‑accuracy structural assessment via AlphaMissense‑Optimized confirms a Benign prediction, while the SGM‑Consensus result is consistent. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar designation and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | Likely Benign | 1 | 6-33443392-G-C | 28 | 1.73e-5 | -6.511 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.156 | Likely Benign | 0.3375 | 0.4957 | -0.41 | Neutral | 0.224 | Benign | 0.131 | Benign | 4.97 | Benign | 0.10 | Tolerated | 4.32 | 4 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||
| c.2843G>C | G948A 2D AIThe SynGAP1 missense variant G948A 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -5.627 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.189 | Likely Benign | 0.3350 | 0.4957 | 0.04 | Neutral | 0.288 | Benign | 0.103 | Benign | 4.64 | Benign | 0.39 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2849G>C | G950A 2D AIThe SynGAP1 missense variant G950A 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.557 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.339 | Likely Benign | 0.3343 | 0.4957 | -0.13 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.28 | Pathogenic | 0.08 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2855G>C | G952A 2D AIThe SynGAP1 missense variant G952A is predicted to be benign by every evaluated in‑silico tool. Benign predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. ClinVar contains no entry for G952A, so there is no conflicting clinical annotation. Overall, the computational evidence indicates the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.796 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.273 | Likely Benign | 0.3309 | 0.4957 | -0.20 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.26 | Benign | 0.08 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3167G>C | G1056A 2D AIThe SynGAP1 missense variant G1056A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -7.458 | In-Between | 0.086 | Likely Benign | Likely Benign | 0.325 | Likely Benign | 0.3325 | 0.4957 | -0.25 | Neutral | 0.264 | Benign | 0.097 | Benign | 1.85 | Pathogenic | 0.49 | Tolerated | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3188G>C | G1063A 2D AIThe SynGAP1 missense variant G1063A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -5.373 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.045 | Likely Benign | 0.3348 | 0.4957 | 0.33 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.12 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3356G>C | G1119A 2D AIThe SynGAP1 missense variant G1119A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -6.703 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.201 | Likely Benign | 0.3591 | 0.4957 | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 3.93 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1048G>C | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L 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, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1173 | 0.4958 | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1048G>T | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L 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, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other tools provide conflicting evidence. Based on the preponderance of predictions, V350L is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1173 | 0.4958 | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.3239C>G | A1080G 2D  AIThe SynGAP1 missense variant A1080G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the consensus of the majority of prediction algorithms and the high‑accuracy tools points to a benign effect for A1080G, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -3.515 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 0.089 | Likely Benign | 0.2153 | 0.4958 | -0.80 | Neutral | 0.901 | Possibly Damaging | 0.355 | Benign | 4.00 | Benign | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3305C>G | A1102G 2D AIThe SynGAP1 A1102G missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as “Likely Benign,” and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. 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 | -3.070 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1947 | 0.4958 | 0.39 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.30 | Pathogenic | 0.14 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.82T>G | S28A 2D AIThe SynGAP1 missense variant S28A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -3.517 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.5194 | 0.4958 | Weaken | 0.09 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.27 | Benign | 1.00 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.3812A>C | E1271A 2D  AIThe SynGAP1 missense variant E1271A is not 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as 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 and the high‑accuracy consensus favor a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.817 | Likely Benign | 0.375 | Ambiguous | Likely Benign | 0.298 | Likely Benign | 0.2985 | 0.4959 | -4.79 | Deleterious | 0.951 | Possibly Damaging | 0.433 | Benign | 2.06 | Pathogenic | 0.00 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.302A>T | H101L 2D AIThe SynGAP1 missense variant H101L 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 H101L, 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 | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -1.376 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.129 | Likely Benign | 0.0924 | 0.4960 | -1.33 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.19 | Benign | 0.00 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.2032A>G | S678G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, REVEL, FoldX, premPS, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is listed as “Uncertain.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -4.379 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.2807 | 0.4961 | 0.24 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.40 | Likely Benign | -0.24 | Likely Benign | 1.90 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.43 | Benign | 1.00 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.2386C>A | P796T 2D AIThe SynGAP1 P796T missense variant is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -5.399 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.1705 | 0.4961 | -0.01 | Neutral | 0.494 | Possibly Damaging | 0.236 | Benign | 4.26 | Benign | 0.04 | Affected | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.2986C>G | P996A 2D  AIThe SynGAP1 missense variant P996A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -4.596 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 0.3242 | 0.4961 | -0.40 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.86 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.3799 | 0.4963 | -0.95 | Neutral | 0.561 | Possibly Damaging | 0.139 | Benign | 2.54 | Benign | 0.79 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2878C>T | H960Y 2D  AIThe SynGAP1 missense variant H960Y is reported in gnomAD (ID 6‑33443430‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity—polyPhen‑2 HumDiv and ESM1b—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 unavailable. Overall, the consensus of the majority of prediction algorithms and the high‑accuracy tools points to a benign effect. 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 | 0.987911 | Disordered | 0.983385 | Binding | 0.380 | 0.901 | 0.750 | 6-33443430-C-T | 1 | 6.20e-7 | -8.181 | Likely Pathogenic | 0.158 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.1446 | 0.4963 | -1.25 | Neutral | 0.748 | Possibly Damaging | 0.232 | Benign | 4.13 | Benign | 0.21 | Tolerated | 3.77 | 5 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.1358A>T | H453L 2D 3DClick to see structure in 3D Viewer AISynGAP1 H453L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, FATHMM, and the protein‑folding stability method Foldetta; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments indicate that AlphaMissense‑Optimized is uncertain, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools, but the presence of several benign calls and the uncertainty of AlphaMissense‑Optimized temper this conclusion. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.438 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.413 | Likely Benign | 0.0841 | 0.4964 | -0.59 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.28 | Likely Benign | 0.31 | Likely Benign | -10.87 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.45 | Benign | 0.11 | Tolerated | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.2487G>C | E829D 2D  AIThe SynGAP1 missense variant E829D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that E829D 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 | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.015 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.1939 | 0.4964 | -1.89 | Neutral | 0.217 | Benign | 0.121 | Benign | 2.40 | Pathogenic | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2487G>T | E829D 2D AIThe SynGAP1 missense variant E829D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that E829D 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 | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.015 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.1939 | 0.4964 | -1.89 | Neutral | 0.217 | Benign | 0.121 | Benign | 2.40 | Pathogenic | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.182A>G | E61G 2D AIThe SynGAP1 missense variant E61G 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) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and the protein‑folding stability tool Foldetta is not available for this variant. Overall, the majority of evidence points to a benign effect. There is no ClinVar entry to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.352862 | Structured | 0.477329 | Uncertain | 0.518 | 0.699 | 0.125 | -5.574 | Likely Benign | 0.469 | Ambiguous | Likely Benign | 0.072 | Likely Benign | 0.3593 | 0.4965 | -1.68 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2391 | 0.4966 | -1.36 | Neutral | 0.998 | Probably Damaging | 0.942 | Probably Damaging | 2.54 | Benign | 0.10 | Tolerated | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.3440C>T | T1147I 2D AIThe SynGAP1 missense variant T1147I is not 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 unavailable. Based on the collective evidence, 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 | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.552 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.423 | Likely Benign | 0.1029 | 0.4968 | -2.03 | Neutral | 0.259 | Benign | 0.059 | Benign | 5.42 | Benign | 0.01 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.109T>G | S37A 2D AIThe SynGAP1 missense variant S37A is not 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, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. 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; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -4.052 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.045 | Likely Benign | 0.5089 | 0.4970 | Weaken | -0.86 | Neutral | 0.140 | Benign | 0.355 | Benign | 3.98 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.2327G>C | G776A 2D AIThe SynGAP1 missense variant G776A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G776A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -5.275 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.173 | Likely Benign | 0.3648 | 0.4971 | -1.82 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 4.26 | Benign | 0.03 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2381C>A | P794Q 2D  AIThe SynGAP1 missense variant P794Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P794Q, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -4.641 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.1581 | 0.4971 | -0.31 | Neutral | 0.918 | Possibly Damaging | 0.601 | Possibly Damaging | 4.24 | Benign | 0.02 | Affected | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||
| c.3329G>T | S1110I 2D AIThe SynGAP1 missense variant S1110I is catalogued in gnomAD (ID 6‑33443881‑G‑T) but has no ClinVar submission. Functional prediction tools show a split: six algorithms (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, whereas three (PROVEAN, SIFT, FATHMM) predict pathogenicity. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized classifies the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic); Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this residue. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | 6-33443881-G-T | -6.124 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.038 | Likely Benign | 0.1203 | 0.4971 | -2.99 | Deleterious | 0.007 | Benign | 0.003 | Benign | 2.17 | Pathogenic | 0.01 | Affected | 4.32 | 2 | -2 | -1 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||
| c.3244C>A | Q1082K 2D  AIThe SynGAP1 missense variant Q1082K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score benign, and AlphaMissense‑Optimized also predicts benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. No tools predict pathogenicity, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, while Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -4.488 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.087 | Likely Benign | 0.2008 | 0.4972 | -1.13 | Neutral | 0.224 | Benign | 0.058 | Benign | 4.19 | Benign | 0.12 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.745G>A | A249T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249T is listed in ClinVar (ID 1031675.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the balance of evidence favors a benign interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | Uncertain | 1 | -3.564 | Likely Benign | 0.805 | Likely Pathogenic | Ambiguous | 0.487 | Likely Benign | 0.0909 | 0.4972 | 1.50 | Ambiguous | 0.6 | 1.39 | Ambiguous | 1.45 | Ambiguous | 0.30 | Likely Benign | -0.96 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.65 | Benign | 0.40 | Tolerated | 3.39 | 15 | 1 | 0 | -2.5 | 30.03 | 214.5 | -43.3 | 0.0 | 0.0 | 0.5 | 0.2 | X | Potentially Benign | The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations. | ||||||||||||
| c.1483G>C | E495Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495Q missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta, all of which score the substitution as benign. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -11.050 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.748 | Likely Pathogenic | 0.1093 | 0.4973 | -0.27 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.08 | Likely Benign | 0.89 | Ambiguous | -2.92 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.331C>T | P111S 2D  AIThe SynGAP1 missense variant P111S 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 also support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the collective predictions strongly suggest that P111S is most likely benign, 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 | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.773 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.3515 | 0.4973 | -1.03 | Neutral | 0.131 | Benign | 0.026 | Benign | 4.21 | Benign | 0.29 | Tolerated | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.718G>A | D240N 2D  AIThe SynGAP1 missense variant D240N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. High‑accuracy methods give a split: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools favor a benign effect, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | Uncertain | 1 | -12.942 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 0.701 | Likely Pathogenic | 0.0993 | 0.4973 | 0.22 | Likely Benign | 0.9 | 0.47 | Likely Benign | 0.35 | Likely Benign | 0.37 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.88 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||
| c.484C>A | R162S 2D  AIThe SynGAP1 missense variant R162S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). AlphaMissense‑Optimized is currently Uncertain, and no Foldetta stability result is available. Overall, the majority of high‑accuracy and consensus predictions indicate a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -1.395 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | 0.3080 | 0.4974 | -0.24 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.14 | Benign | 0.75 | Tolerated | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| c.926G>C | G309A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G309A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and Rosetta, whereas pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Foldetta, premPS, and ESM1b. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, while Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for G309A. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -7.980 | In-Between | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.373 | Likely Benign | 0.3949 | 0.4974 | 2.44 | Destabilizing | 0.4 | 0.30 | Likely Benign | 1.37 | Ambiguous | 0.71 | Ambiguous | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.69 | Pathogenic | 0.09 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.437C>T | S146L 2D  AIThe SynGAP1 missense variant S146L is not 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 FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) which 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 majority of predictions indicate a pathogenic 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 Pathogenic | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -15.179 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.130 | Likely Benign | 0.0856 | 0.4975 | -3.77 | Deleterious | 0.084 | Benign | 0.063 | Benign | 3.63 | Benign | 0.00 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.1220A>T | Q407L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407L is not 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, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Four tools are uncertain (AlphaMissense‑Default, FoldX, Rosetta, Foldetta). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools predict pathogenicity than benign, and the high‑accuracy consensus leans pathogenic. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -12.730 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | 0.359 | Likely Benign | 0.0585 | 0.4977 | -0.65 | Ambiguous | 0.2 | -0.69 | Ambiguous | -0.67 | Ambiguous | 0.35 | Likely Benign | -6.32 | Deleterious | 0.939 | Possibly Damaging | 0.838 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||
| c.2021C>A | T674N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674N is not 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome; ESM1b is uncertain and does not influence the consensus. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. No contradictory evidence is present. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not conflict with the ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -7.839 | In-Between | 0.135 | Likely Benign | Likely Benign | 0.119 | Likely Benign | 0.1263 | 0.4979 | -0.21 | Likely Benign | 0.0 | 0.15 | Likely Benign | -0.03 | Likely Benign | 0.19 | Likely Benign | -0.71 | Neutral | 0.958 | Probably Damaging | 0.671 | Possibly Damaging | 3.44 | Benign | 0.17 | Tolerated | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||
| c.3674C>T | S1225F 2D AIThe SynGAP1 missense variant S1225F 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, 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 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 S1225F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -7.938 | In-Between | 0.328 | Likely Benign | Likely Benign | 0.423 | Likely Benign | 0.0505 | 0.4979 | -2.34 | Neutral | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 5.37 | Benign | 0.06 | Tolerated | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||
| c.527G>C | S176T 2D AIThe SynGAP1 missense variant S176T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, 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 | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -3.682 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.045 | Likely Benign | 0.1103 | 0.4979 | -0.73 | Neutral | 0.421 | Benign | 0.054 | Benign | 4.09 | Benign | 0.19 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1370G>A | S457N 2D  AIThe SynGAP1 missense variant S457N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy Foldetta result suggests a benign impact. Thus, the variant is most likely pathogenic based on the preponderance of predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | Uncertain | 1 | -10.221 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.1015 | 0.4980 | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||
| c.3170G>T | S1057I 2D AIThe SynGAP1 missense variant S1057I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments 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 points to the variant being 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 | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.887 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.259 | Likely Benign | 0.1802 | 0.4980 | -0.87 | Neutral | 0.925 | Possibly Damaging | 0.238 | Benign | 5.24 | Benign | 0.07 | Tolerated | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.2210A>C | Q737P 2D  AIThe SynGAP1 missense variant Q737P is listed in ClinVar (ID 2580571.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Taken together, the preponderance of evidence supports a benign classification for Q737P, 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | Uncertain | 1 | -2.407 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.154 | Likely Benign | 0.2366 | 0.4981 | -1.22 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.78 | Benign | 0.04 | Affected | 4.07 | 3 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||
| c.1595C>T | T532I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) reports a benign effect. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -9.031 | Likely Pathogenic | 0.591 | Likely Pathogenic | Likely Benign | 0.428 | Likely Benign | 0.0713 | 0.4983 | -0.11 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.38 | Likely Benign | 0.22 | Likely Benign | -3.31 | Deleterious | 0.633 | Possibly Damaging | 0.202 | Benign | -1.31 | Pathogenic | 0.03 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.2788C>G | P930A 2D AIThe SynGAP1 missense variant P930A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). 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. 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. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that P930A 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 | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -8.938 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.392 | Likely Benign | 0.3376 | 0.4983 | -6.03 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3989A>C | Q1330P 2D AIThe SynGAP1 missense variant Q1330P is listed in gnomAD (ID 6‑33451863‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an “Uncertain” result, SGM‑Consensus confirms a benign leaning, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence favors a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | 6-33451863-A-C | -3.087 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.076 | Likely Benign | 0.2266 | 0.4983 | -2.45 | Neutral | 0.898 | Possibly Damaging | 0.441 | Benign | 3.91 | Benign | 0.03 | Affected | 3.77 | 5 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||
| c.4018A>C | T1340P 2D  AIThe SynGAP1 missense variant T1340P is catalogued in gnomAD (ID 6‑33451892‑A‑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 report benign or tolerated outcomes, while only SIFT predicts a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that T1340P 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 | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451892-A-C | -2.681 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.190 | Likely Benign | 0.2268 | 0.4983 | -1.81 | Neutral | 0.334 | Benign | 0.099 | Benign | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 0 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||
| c.2336G>A | S779N 2D AIThe SynGAP1 missense variant S779N is listed in gnomAD (ID 6‑33442494‑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, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign majority. The AlphaMissense‑Optimized score is benign, and no Foldetta stability assessment is available. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | 6-33442494-G-A | -4.880 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.087 | Likely Benign | 0.1327 | 0.4984 | -0.75 | Neutral | 0.021 | Benign | 0.026 | Benign | 2.30 | Pathogenic | 0.23 | Tolerated | 3.64 | 6 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||
| 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 | 0.1271 | 0.4984 | -0.85 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.64 | Benign | 0.30 | Tolerated | 4.32 | 4 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||
| c.314C>G | S105W 2D  AIThe SynGAP1 missense variant S105W is catalogued in gnomAD (ID 6‑33432179‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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 | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | 6-33432179-C-G | 2 | 1.24e-6 | -5.600 | Likely Benign | 0.606 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | 0.0705 | 0.4984 | -2.28 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1162G>A | G388S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G388S is catalogued in gnomAD (ID 6‑33438067‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that converge on a pathogenic interpretation are FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. In contrast, the protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a pathogenic effect. No prediction is available from Rosetta alone, and the SGM‑Consensus result aligns with the benign consensus. Overall, the majority of evidence points to a benign impact, 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 | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | 6-33438067-G-A | 1 | 6.21e-7 | -5.036 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.446 | Likely Benign | 0.2901 | 0.4985 | 3.42 | Destabilizing | 3.5 | 1.69 | Ambiguous | 2.56 | Destabilizing | 0.18 | Likely Benign | -0.52 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 4.32 | 3 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||
| 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 | 0.2052 | 0.4985 | -0.60 | Neutral | 0.998 | Probably Damaging | 0.924 | Probably Damaging | 2.59 | Benign | 0.04 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3086A>C | Q1029P 2D AIThe SynGAP1 missense variant Q1029P is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available for this variant. Overall, the consensus of all available predictions strongly supports a benign impact, 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -2.940 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.1966 | 0.4986 | -1.23 | Neutral | 0.005 | Benign | 0.015 | Benign | 2.68 | Benign | 0.15 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.878G>T | R293L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and premPS, while the remaining evaluated tools (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. Uncertain results from FoldX, Rosetta, and Foldetta are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta provides no definitive stability change. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, 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 Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | -15.502 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | 0.1815 | 0.4987 | 1.56 | Ambiguous | 0.2 | 0.93 | Ambiguous | 1.25 | Ambiguous | 0.08 | Likely Benign | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.46 | Pathogenic | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.2575A>G | S859G 2D AIThe SynGAP1 missense variant S859G is not reported in ClinVar and is absent from gnomAD. In silico predictions cluster into three groups: benign (REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized), pathogenic (polyPhen‑2 HumDiv and HumVar), and uncertain (ESM1b). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy tools further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for S859G, 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 | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -7.412 | In-Between | 0.087 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.2798 | 0.4988 | -0.69 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 4.00 | Benign | 0.25 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3913A>T | T1305S 2D AIThe SynGAP1 missense variant T1305S 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 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 | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -2.813 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.3683 | 0.4988 | 0.20 | Neutral | 0.003 | Benign | 0.026 | Benign | 2.83 | Benign | 0.08 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.385T>C | S129P 2D AIThe SynGAP1 missense variant S129P 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 | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -2.469 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.220 | Likely Benign | 0.1998 | 0.4989 | -0.09 | Neutral | 0.454 | Possibly Damaging | 0.133 | Benign | 4.11 | Benign | 0.32 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.719A>G | D240G 2D AIThe SynGAP1 missense variant D240G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by premPS and FATHMM, whereas pathogenic predictions are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy methods show that AlphaMissense‑Optimized is inconclusive, SGM Consensus predicts pathogenic, and Foldetta predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | Uncertain | 1 | -12.825 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.912 | Likely Pathogenic | 0.3474 | 0.4989 | 1.85 | Ambiguous | 0.1 | 2.72 | Destabilizing | 2.29 | Destabilizing | 0.24 | Likely Benign | -6.19 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||
| c.2977C>G | P993A 2D AIThe SynGAP1 missense variant P993A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.030 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 0.3487 | 0.4991 | -0.46 | Neutral | 0.001 | Benign | 0.006 | Benign | 4.26 | Benign | 0.07 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2018 | 0.4992 | -3.43 | Deleterious | 0.001 | Benign | 0.010 | Benign | 2.58 | Benign | 0.00 | Affected | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.719A>C | D240A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D240A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently flag the variant as deleterious. Tools with uncertain outcomes (FoldX, Rosetta, Foldetta) provide no definitive guidance. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -12.935 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.872 | Likely Pathogenic | 0.3317 | 0.4992 | 0.75 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.87 | Ambiguous | 0.22 | Likely Benign | -7.03 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.80 | Benign | 0.05 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.1105A>T | T369S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -2.018 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.3746 | 0.4994 | -0.07 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.14 | Likely Benign | 0.18 | Likely Benign | -0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.78 | Pathogenic | 0.39 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.3288G>C | E1096D 2D AIThe SynGAP1 missense variant E1096D 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 interpretation, 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.818 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2034 | 0.4994 | -0.40 | Neutral | 0.115 | Benign | 0.052 | Benign | 2.71 | Benign | 0.38 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3288G>T | E1096D 2D AIThe SynGAP1 missense variant E1096D 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 is not contradicted by 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.818 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2034 | 0.4994 | -0.40 | Neutral | 0.115 | Benign | 0.052 | Benign | 2.71 | Benign | 0.38 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.670A>T | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.412 | Likely Benign | 0.3498 | 0.4994 | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.671C>G | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.374 | Likely Benign | 0.3498 | 0.4994 | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.373C>A | P125T 2D AIThe SynGAP1 missense variant P125T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -4.780 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.215 | Likely Benign | 0.1502 | 0.4995 | -3.78 | Deleterious | 0.036 | Benign | 0.014 | Benign | 2.85 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.1075A>T | T359S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T359S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome, while FoldX, Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also favors benign. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | -4.624 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.3637 | 0.4996 | 0.50 | Ambiguous | 0.0 | 0.73 | Ambiguous | 0.62 | Ambiguous | 0.66 | Ambiguous | -1.87 | Neutral | 0.146 | Benign | 0.024 | Benign | 1.76 | Pathogenic | 0.27 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.3833C>T | P1278L 2D AIThe SynGAP1 missense variant P1278L is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.903 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.140 | Likely Benign | 0.2338 | 0.4996 | -1.86 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.69 | Benign | 0.07 | Tolerated | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.133A>G | N45D 2D AIThe SynGAP1 missense variant N45D 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; no Foldetta stability result is available. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—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 | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -3.340 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.2234 | 0.4999 | -0.37 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.578C>G | A193G 2D AIThe SynGAP1 missense variant A193G is not 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, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and 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 (5) than benignity (3), 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. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.822 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | 0.2283 | 0.4999 | -2.61 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3485C>A | P1162H 2D AIThe SynGAP1 missense variant P1162H is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as Pathogenic, whereas the SGM‑Consensus (majority vote) indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) lean toward a benign interpretation, but the high‑accuracy AlphaMissense‑Optimized prediction conflicts with the consensus. Because ClinVar contains no entry, there is no contradiction with clinical database status. Based on the collective predictions, the variant is most likely benign, though the AlphaMissense‑Optimized result suggests caution. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -3.733 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.168 | Likely Benign | 0.1481 | 0.5001 | -2.46 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.67 | Benign | 0.17 | Tolerated | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.230G>C | S77T 2D AIThe SynGAP1 missense variant S77T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of computational evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -4.204 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.1180 | 0.5003 | -0.03 | Neutral | 0.092 | Benign | 0.007 | Benign | 4.19 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1713 | 0.5004 | -1.16 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.61 | Benign | 0.23 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3550T>A | S1184T 2D AIThe SynGAP1 missense variant S1184T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.648219 | Disordered | 0.514669 | Binding | 0.624 | 0.642 | 0.500 | -4.250 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | 0.1212 | 0.5004 | -1.27 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.70 | Benign | 0.18 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.35G>A | S12N 2D AIThe SynGAP1 missense variant S12N is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33420299‑G‑A). Functional 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. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | 6-33420299-G-A | -4.946 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 0.1405 | 0.5004 | -0.41 | Neutral | 0.208 | Benign | 0.018 | Benign | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
| c.3836C>T | A1279V 2D AIThe SynGAP1 missense variant A1279V is reported in gnomAD (ID 6‑33447884‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions appear in the dataset, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a benign score, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Taken together, the consensus of all available predictions is that A1279V is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447884-C-T | -4.892 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.0777 | 0.5005 | -1.23 | Neutral | 0.017 | Benign | 0.017 | Benign | 2.68 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.92G>C | R31P 2D AIThe SynGAP1 missense variant R31P 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 further support a benign classification: 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 for R31P, 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 | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.185 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.209 | Likely Benign | 0.2220 | 0.5005 | -1.64 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.1346G>T | S449I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. Rosetta and Foldetta give uncertain results. 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 also remains uncertain. Overall, the majority of evidence (7 benign vs. 3 pathogenic) points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -9.549 | Likely Pathogenic | 0.310 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.0756 | 0.5006 | 0.04 | Likely Benign | 0.1 | -1.39 | Ambiguous | -0.68 | Ambiguous | 0.13 | Likely Benign | -3.23 | Deleterious | 0.559 | Possibly Damaging | 0.044 | Benign | 3.40 | Benign | 0.14 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||
| c.16G>C | A6P 2D AIThe SynGAP1 missense variant A6P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the 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 | 0.566480 | Disordered | 0.549054 | Binding | 0.377 | 0.920 | 0.875 | -3.440 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.2093 | 0.5007 | -0.12 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.06 | Benign | 0.00 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3994A>T | T1332S 2D AIThe SynGAP1 missense variant T1332S is reported in gnomAD (ID 6‑33451868‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Benign” (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, 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 not contradicted by ClinVar, which contains no classification for T1332S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | 6-33451868-A-T | -3.085 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | 0.3451 | 0.5007 | -2.29 | Neutral | 0.980 | Probably Damaging | 0.935 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||
| c.1027G>C | V343L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only FATHMM predicts a pathogenic outcome, while FoldX and Rosetta provide uncertain results and are therefore not considered decisive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -6.268 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.1361 | 0.5008 | -0.93 | Ambiguous | 0.2 | 0.66 | Ambiguous | -0.14 | Likely Benign | 0.16 | Likely Benign | -1.09 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.12 | Pathogenic | 0.64 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.862G>T | D288Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, and premPS; pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the available tools suggests a benign 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 | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -15.269 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.472 | Likely Benign | 0.0635 | 0.5009 | 0.11 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.61 | Ambiguous | 0.10 | Likely Benign | -7.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.2159A>G | D720G 2D AISynGAP1 missense variant D720G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools remain inconclusive: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -11.130 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.427 | Likely Benign | 0.4027 | 0.5011 | 0.45 | Likely Benign | 0.4 | 0.53 | Ambiguous | 0.49 | Likely Benign | 0.46 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.15 | Pathogenic | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.537G>C | E179D 2D AIThe SynGAP1 missense variant E179D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote, and Foldetta data are unavailable. Overall, the balance of evidence (four benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) indicates 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. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -7.741 | In-Between | 0.929 | Likely Pathogenic | Ambiguous | 0.145 | Likely Benign | 0.2327 | 0.5011 | -1.91 | Neutral | 0.596 | Possibly Damaging | 0.142 | Benign | 3.97 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.537G>T | E179D 2D AIThe SynGAP1 missense variant E179D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote, and Foldetta data are unavailable. Overall, the balance of evidence (four benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) indicates that the variant is most likely benign. 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. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -7.741 | In-Between | 0.929 | Likely Pathogenic | Ambiguous | 0.145 | Likely Benign | 0.2327 | 0.5011 | -1.91 | Neutral | 0.596 | Possibly Damaging | 0.142 | Benign | 3.97 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.1345A>T | S449C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449C is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -2.207 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.0864 | 0.5012 | 0.48 | Likely Benign | 0.0 | -0.31 | Likely Benign | 0.09 | Likely Benign | -0.57 | Ambiguous | 0.48 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.32 | Benign | 0.21 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.121C>A | R41S 2D AIThe SynGAP1 missense variant R41S is not 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 R41S, 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 | 0.311707 | Structured | 0.431757 | Uncertain | 0.344 | 0.765 | 0.375 | -3.367 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.130 | Likely Benign | 0.3190 | 0.5013 | -0.22 | Neutral | 0.686 | Possibly Damaging | 0.735 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0605 | 0.5014 | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.682A>G | T228A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228A variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), 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 effect are REVEL, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as benign (majority of its constituent predictors are benign), and Foldetta as uncertain. Overall, the balance of evidence favors a benign interpretation; 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 | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -5.190 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.520 | Likely Pathogenic | 0.4072 | 0.5014 | 0.44 | Likely Benign | 0.0 | 0.82 | Ambiguous | 0.63 | Ambiguous | 0.58 | Ambiguous | -2.30 | Neutral | 0.363 | Benign | 0.138 | Benign | 5.63 | Benign | 0.04 | Affected | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.989A>G | D330G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two predictors (AlphaMissense‑Optimized and premPS) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that D330G is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -13.064 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.373 | Likely Benign | 0.3935 | 0.5015 | 2.69 | Destabilizing | 0.2 | 2.17 | Destabilizing | 2.43 | Destabilizing | 0.63 | Ambiguous | -5.03 | Deleterious | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 0.94 | Pathogenic | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| 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 | 0.3820 | 0.5016 | -2.37 | Neutral | 0.770 | Possibly Damaging | 0.303 | Benign | 2.46 | Pathogenic | 0.02 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.2902G>C | G968R 2D AIThe SynGAP1 missense variant G968R 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 evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -4.492 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.140 | Likely Benign | 0.0972 | 0.5017 | -0.63 | Neutral | 0.005 | Benign | 0.012 | Benign | 4.19 | Benign | 0.08 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3480C>A | N1160K 2D  AIThe SynGAP1 missense variant N1160K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this residue. 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 | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.768 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | 0.1919 | 0.5017 | -3.92 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.04 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||
| c.3480C>G | N1160K 2D AIThe SynGAP1 missense variant N1160K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this residue. 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 | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.768 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.189 | Likely Benign | 0.1919 | 0.5017 | -3.92 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.04 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||
| c.1333G>C | E445Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445Q is reported in gnomAD (ID 6‑33438238‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b). Two tools remain inconclusive (premPS, AlphaMissense‑Optimized). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; 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 stability outputs, predicts a benign impact. Overall, the balance of evidence tilts toward pathogenicity, with the high‑accuracy consensus supporting this view, and there is no conflict with ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | 6-33438238-G-C | 1 | 6.19e-7 | -12.430 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.240 | Likely Benign | 0.0787 | 0.5018 | -0.03 | Likely Benign | 0.0 | 0.20 | Likely Benign | 0.09 | Likely Benign | 0.70 | Ambiguous | -2.86 | Deleterious | 0.987 | Probably Damaging | 0.946 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.38 | 31 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.3923G>C | R1308P 2D AIThe SynGAP1 missense variant R1308P is not reported in ClinVar but is present in gnomAD (ID 6‑33451797‑G‑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 a 2‑vs‑2 split and therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Because the available predictions are evenly divided between benign and pathogenic, the overall computational assessment is inconclusive; the variant is neither clearly benign nor clearly pathogenic. This lack of consensus does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | 6-33451797-G-C | -1.320 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.158 | Likely Benign | 0.2070 | 0.5020 | -4.62 | Deleterious | 0.995 | Probably Damaging | 0.992 | Probably Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||
| c.2765G>T | R922L 2D AIThe SynGAP1 missense variant R922L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign interpretation. Therefore, the variant is most likely benign according to the consensus of predictive tools, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -3.714 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 0.150 | Likely Benign | 0.2033 | 0.5022 | 0.84 | Neutral | 0.983 | Probably Damaging | 0.828 | Possibly Damaging | 3.04 | Benign | 1.00 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0756 | 0.5023 | -3.33 | Deleterious | 0.057 | Benign | 0.053 | Benign | 2.51 | Benign | 0.03 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.314C>T | S105L 2D AIThe SynGAP1 missense variant S105L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432179‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy methods both support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | Uncertain | 2 | 6-33432179-C-T | 4 | 2.48e-6 | -3.710 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.1161 | 0.5023 | -1.52 | Neutral | 0.828 | Possibly Damaging | 0.048 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||
| c.106C>T | H36Y 2D AIThe SynGAP1 missense variant H36Y is listed in ClinVar with an uncertain significance (ClinVar ID 2089635.0) and is present in the gnomAD database (gnomAD ID 6‑33423515‑C‑T). Functional prediction tools largely agree that the substitution is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. No Foldetta stability prediction is available. Overall, the computational evidence overwhelmingly supports a benign classification, which is consistent with the ClinVar designation of uncertain significance rather than a pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.433974 | Uncertain | 0.334 | 0.834 | 0.375 | Uncertain | 1 | 6-33423515-C-T | 2 | 1.24e-6 | -3.461 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.023 | Likely Benign | 0.1265 | 0.5024 | -1.03 | Neutral | 0.219 | Benign | 0.066 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||
| c.25C>T | H9Y 2D AIThe SynGAP1 missense variant H9Y is reported in gnomAD (ID 6‑33420289‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is likely benign. 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 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 | 0.486429 | Structured | 0.528099 | Binding | 0.394 | 0.916 | 0.750 | 6-33420289-C-T | -3.833 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.1227 | 0.5024 | -0.14 | Neutral | 0.047 | Benign | 0.006 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||
| c.292C>T | H98Y 2D AIThe SynGAP1 missense variant H98Y is not 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 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 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 | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -4.050 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 0.0950 | 0.5024 | -0.86 | Neutral | 0.444 | Benign | 0.024 | Benign | 4.19 | Benign | 0.00 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.4003G>C | G1335R 2D AIThe SynGAP1 missense variant G1335R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are not available. Overall, the preponderance of evidence supports a pathogenic classification for G1335R, 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 | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.921 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | 0.1071 | 0.5024 | -5.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.1769G>T | S590I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include FoldX, premPS, and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Rosetta and Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that S590I 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 | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -17.956 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.686 | Likely Pathogenic | 0.0975 | 0.5025 | -0.04 | Likely Benign | 0.5 | 1.15 | Ambiguous | 0.56 | Ambiguous | 0.31 | Likely Benign | -5.78 | Deleterious | 0.998 | Probably Damaging | 0.948 | Probably Damaging | 3.05 | Benign | 0.02 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| 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 | 0.3490 | 0.5025 | -1.54 | Neutral | 0.989 | Probably Damaging | 0.829 | Possibly Damaging | 2.43 | Pathogenic | 0.08 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.494G>T | S165I 2D AISynGAP1 missense variant S165I has no ClinVar record and is absent from gnomAD. Individual prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, 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 show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the majority of single‑tool predictions favor a benign effect, whereas the consensus score suggests pathogenicity. Consequently, the variant is most likely benign according to the bulk of evidence, 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 Pathogenic | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -11.304 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.259 | Likely Benign | 0.0943 | 0.5027 | -2.53 | Deleterious | 0.084 | Benign | 0.031 | Benign | 3.96 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1363 | 0.5028 | -1.12 | Neutral | 0.784 | Possibly Damaging | 0.316 | Benign | 2.51 | Benign | 0.04 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| 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 | 0.1798 | 0.5029 | -1.37 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.3999G>C | E1333D 2D AIThe SynGAP1 missense variant E1333D 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, 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 E1333D, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.239 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | 0.1989 | 0.5029 | -1.78 | Neutral | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3999G>T | E1333D 2D AIThe SynGAP1 missense variant E1333D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT classify the change as pathogenic, and AlphaMissense‑Default also predicts pathogenicity. High‑accuracy tools specifically give a benign prediction for AlphaMissense‑Optimized and a likely benign result for the SGM‑Consensus; Foldetta data are unavailable. Overall, the majority of evidence supports a benign interpretation, and this is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and this is consistent with the lack of a ClinVar pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.239 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | 0.1989 | 0.5029 | -1.78 | Neutral | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.544T>C | S182P 2D AIThe SynGAP1 missense variant S182P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates 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 independent predictors 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 | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -13.362 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.279 | Likely Benign | 0.2438 | 0.5030 | -3.71 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.67 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.286G>C | G96R 2D AIThe SynGAP1 missense variant G96R is not 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, 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 G96R, 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 | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | -3.872 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.059 | Likely Benign | 0.1300 | 0.5031 | -0.91 | Neutral | 0.687 | Possibly Damaging | 0.062 | Benign | 4.19 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.1067G>C | R356P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R356P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R356P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -12.956 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.451 | Likely Benign | 0.2213 | 0.5033 | 0.48 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.60 | Ambiguous | 1.05 | Destabilizing | -6.23 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.72 | Pathogenic | 0.02 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.2570G>A | S857N 2D AIThe SynGAP1 missense variant S857N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -5.065 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.1515 | 0.5034 | 0.24 | Neutral | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 4.09 | Benign | 1.00 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.3113C>T | T1038I 2D AIThe SynGAP1 T1038I missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as Likely Benign. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with one high‑accuracy tool inconclusive and no conflicting ClinVar annotation. Thus, the variant is most likely benign, and there is no ClinVar status that contradicts this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -4.552 | Likely Benign | 0.877 | Likely Pathogenic | Ambiguous | 0.093 | Likely Benign | 0.1012 | 0.5036 | -2.02 | Neutral | 0.990 | Probably Damaging | 0.637 | Possibly Damaging | 2.69 | Benign | 0.04 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.2863T>G | S955A 2D AIThe SynGAP1 missense variant S955A is not 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 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 | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -4.258 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.4262 | 0.5038 | -0.71 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.41 | Pathogenic | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.481C>A | P161T 2D AIThe SynGAP1 missense variant P161T has no ClinVar entry and is not reported in gnomAD. Computational predictors fall into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also 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 assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.509769 | Disordered | 0.520000 | Binding | 0.256 | 0.713 | 0.375 | -8.759 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.153 | Likely Benign | 0.1891 | 0.5038 | -3.77 | Deleterious | 0.535 | Possibly Damaging | 0.310 | Benign | 3.92 | Benign | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.1483G>A | E495K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas 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 is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1974 | 0.5039 | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||
| 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 | 0.0688 | 0.5039 | -3.36 | Deleterious | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||
| c.368C>G | A123G 2D AIThe SynGAP1 missense variant A123G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -2.799 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.2070 | 0.5039 | -1.34 | Neutral | 0.421 | Benign | 0.074 | Benign | 4.13 | Benign | 0.03 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3767A>G | D1256G 2D AIThe SynGAP1 missense variant D1256G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the benign‑predicting REVEL score, and a consensus of pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenicity. Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic effect for D1256G. This conclusion is consistent with the absence 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 | 0.549308 | Disordered | 0.445789 | Uncertain | 0.876 | 0.571 | 0.625 | -11.341 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.457 | Likely Benign | 0.2886 | 0.5040 | -5.45 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||
| c.2362T>G | S788A 2D AIThe SynGAP1 missense variant S788A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for S788A. This consensus does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | -5.381 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.5079 | 0.5041 | Strenghten | -2.24 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 1.59 | Pathogenic | 0.02 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||
| c.3077A>G | D1026G 2D AIThe SynGAP1 missense variant D1026G is not 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, 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 (two benign, two pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of 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. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.125 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.098 | Likely Benign | 0.3377 | 0.5042 | -2.84 | Deleterious | 0.001 | Benign | 0.005 | Benign | 2.67 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.460A>T | S154C 2D AIThe SynGAP1 missense variant S154C is not 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 Foldetta results are unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. With the majority of evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -7.728 | In-Between | 0.244 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.1288 | 0.5042 | -1.83 | Neutral | 0.997 | Probably Damaging | 0.841 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2437 | 0.5044 | -2.29 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.50 | Benign | 0.09 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| c.1064G>C | G355A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G355A missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX and Foldetta are uncertain and therefore not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is uncertain. Consequently, the overall prediction leans toward a benign effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -5.431 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.286 | Likely Benign | 0.4111 | 0.5045 | 0.88 | Ambiguous | 0.6 | 0.46 | Likely Benign | 0.67 | Ambiguous | 0.49 | Likely Benign | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.03 | Affected | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||
| c.877C>A | R293S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that are inconclusive or uncertain are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus indicating a likely pathogenic outcome, while Foldetta’s stability analysis remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic impact for R293S. This conclusion is consistent with the lack of ClinVar annotation, as there is no conflicting status to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | -14.103 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.561 | Likely Pathogenic | 0.2794 | 0.5045 | 2.66 | Destabilizing | 0.2 | 1.30 | Ambiguous | 1.98 | Ambiguous | 0.71 | Ambiguous | -5.52 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.51 | Pathogenic | 0.01 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.1411T>A | S471T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.780 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.257 | Likely Benign | 0.1307 | 0.5046 | 0.59 | Ambiguous | 0.2 | -0.47 | Likely Benign | 0.06 | Likely Benign | 0.20 | Likely Benign | -1.96 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.18 | Pathogenic | 0.09 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.2624C>G | A875G 2D AIThe SynGAP1 missense variant A875G 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 predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates 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 consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -2.904 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.078 | Likely Benign | 0.2308 | 0.5046 | -1.22 | Neutral | 0.022 | Benign | 0.048 | Benign | 2.68 | Benign | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3157A>G | S1053G 2D AIThe SynGAP1 missense variant S1053G is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that S1053G is most likely benign, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -1.016 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.220 | Likely Benign | 0.2724 | 0.5046 | -0.57 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.32 | Benign | 0.59 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.1184G>C | G395A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G395A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX and Rosetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -3.964 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.3848 | 0.5047 | 1.51 | Ambiguous | 0.3 | -0.59 | Ambiguous | 0.46 | Likely Benign | 0.08 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.24 | Benign | 0.15 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.602A>G | D201G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201G 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, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.744 | In-Between | 0.603 | Likely Pathogenic | Likely Benign | 0.289 | Likely Benign | 0.3268 | 0.5047 | 0.71 | Ambiguous | 0.0 | 2.64 | Destabilizing | 1.68 | Ambiguous | 0.24 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.09 | Benign | 0.39 | Tolerated | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||
| c.350G>T | S117I 2D AIThe SynGAP1 missense variant S117I is not 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 remains uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method, 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -5.483 | Likely Benign | 0.559 | Ambiguous | Likely Benign | 0.137 | Likely Benign | 0.1060 | 0.5048 | -2.33 | Neutral | 0.971 | Probably Damaging | 0.598 | Possibly Damaging | 3.70 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.65G>T | R22I 2D  AIThe SynGAP1 missense variant R22I is not 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, 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 balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | -4.849 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | 0.2120 | 0.5048 | 0.06 | Neutral | 0.676 | Possibly Damaging | 0.308 | Benign | 4.20 | Benign | 0.00 | Affected | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.1342G>A | A448T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that A448T 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 | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.192 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.558 | Likely Pathogenic | 0.1187 | 0.5050 | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.2488C>G | P830A 2D AIThe SynGAP1 missense variant P830A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise 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 likewise indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which contains no entry for P830A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.618152 | Binding | 0.333 | 0.874 | 0.500 | -4.471 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.202 | Likely Benign | 0.3534 | 0.5050 | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.82 | Benign | 0.04 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3827A>C | D1276A 2D AIThe SynGAP1 missense variant D1276A 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 score (Likely Pathogenic). High‑accuracy assessments further support this split: AlphaMissense‑Optimized reports a benign effect, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. No Foldetta stability analysis is available for this residue. Overall, the majority of computational evidence points to a pathogenic impact, 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. | Likely Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.008 | Likely Benign | 0.710 | Likely Pathogenic | Likely Benign | 0.319 | Likely Benign | 0.3458 | 0.5050 | -5.87 | Deleterious | 0.816 | Possibly Damaging | 0.495 | Possibly Damaging | 1.21 | Pathogenic | 0.00 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||
| c.602A>C | D201A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201A variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic, and Foldetta remains inconclusive. Overall, the majority of standard tools favor a benign classification, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s impact uncertain. The predictions do not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.793 | In-Between | 0.769 | Likely Pathogenic | Likely Benign | 0.261 | Likely Benign | 0.3177 | 0.5050 | 0.45 | Likely Benign | 0.1 | 1.86 | Ambiguous | 1.16 | Ambiguous | 0.23 | Likely Benign | -3.81 | Deleterious | 0.989 | Probably Damaging | 0.828 | Possibly Damaging | 4.11 | Benign | 0.09 | Tolerated | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||
| 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 | 0.0814 | 0.5051 | -2.29 | Neutral | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.55 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.1757A>G | D586G 2D 3DClick to see structure in 3D Viewer AISynGAP1 D586G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and SIFT, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that 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 | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -8.497 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 0.833 | Likely Pathogenic | 0.3334 | 0.5052 | 1.37 | Ambiguous | 0.3 | 2.49 | Destabilizing | 1.93 | Ambiguous | 0.34 | Likely Benign | -4.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.1105A>G | T369A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T369A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and Foldetta are inconclusive. 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, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that T369A is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -1.957 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.4538 | 0.5053 | 0.09 | Likely Benign | 0.1 | 1.18 | Ambiguous | 0.64 | Ambiguous | 0.26 | Likely Benign | -1.93 | Neutral | 0.012 | Benign | 0.016 | Benign | 1.72 | Pathogenic | 0.30 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1118G>C | G373A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373A is not reported in ClinVar and is absent from gnomAD. Functional prediction consensus shows a predominance of benign calls: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict a benign effect. Pathogenic predictions are limited to SIFT and FoldX, while Rosetta and Foldetta yield uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta remains inconclusive. Overall, the majority of evidence indicates that G373A 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 | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | -5.181 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.227 | Likely Benign | 0.4172 | 0.5053 | 2.44 | Destabilizing | 0.8 | 0.69 | Ambiguous | 1.57 | Ambiguous | -0.01 | Likely Benign | -0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.93 | Benign | 0.01 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1169G>C | G390A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and Rosetta. The high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as pathogenic. FoldX alone is inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -6.768 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.402 | Likely Benign | 0.4130 | 0.5053 | 1.96 | Ambiguous | 0.4 | 2.03 | Destabilizing | 2.00 | Destabilizing | 0.02 | Likely Benign | -0.55 | Neutral | 0.143 | Benign | 0.028 | Benign | 1.33 | Pathogenic | 0.05 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.20C>A | S7Y 2D AIThe SynGAP1 missense variant S7Y 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -5.240 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.193 | Likely Benign | 0.0708 | 0.5053 | -0.36 | Neutral | 0.561 | Possibly Damaging | 0.047 | Benign | 4.06 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.670A>G | T224A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33435521‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. The remaining tools (Rosetta, Foldetta, premPS, ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a 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. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | Uncertain | 3 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.464 | Likely Benign | 0.4253 | 0.5053 | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.1211C>G | A404G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404G is not 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. Tools that predict a pathogenic effect are premPS and SIFT. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results and are treated as unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points to a benign impact for A404G, 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 Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -5.277 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.2370 | 0.5054 | 0.92 | Ambiguous | 0.0 | 1.88 | Ambiguous | 1.40 | Ambiguous | 1.18 | Destabilizing | -2.34 | Neutral | 0.045 | Benign | 0.013 | Benign | 4.03 | Benign | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.875C>G | A292G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A292G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, whereas the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and individual FoldX and Rosetta predictions are also inconclusive. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -9.692 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.323 | Likely Benign | 0.2187 | 0.5054 | 0.88 | Ambiguous | 0.1 | 1.83 | Ambiguous | 1.36 | Ambiguous | 1.05 | Destabilizing | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.74 | Pathogenic | 0.10 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.902C>G | A301G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as Benign. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar claim. Therefore, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.085 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.2425 | 0.5054 | 0.27 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.31 | Likely Benign | 0.37 | Likely Benign | -0.37 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.18 | Benign | 0.28 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1729G>T | A577S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -4.417 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.342 | Likely Benign | 0.2763 | 0.5056 | 0.10 | Likely Benign | 0.0 | 0.60 | Ambiguous | 0.35 | Likely Benign | 0.05 | Likely Benign | -0.30 | Neutral | 0.981 | Probably Damaging | 0.992 | Probably Damaging | -1.24 | Pathogenic | 0.80 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| 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 | 0.1236 | 0.5056 | -2.09 | Neutral | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 2.59 | Benign | 0.02 | Affected | 3.64 | 6 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||
| c.824C>T | P275L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275L is not reported in ClinVar and is absent from gnomAD. In silico predictions cluster into two groups: benign predictions come from REVEL, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of tools predict pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. This prediction does not contradict any ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | -9.785 | Likely Pathogenic | 0.304 | Likely Benign | Likely Benign | 0.430 | Likely Benign | 0.2139 | 0.5056 | 1.63 | Ambiguous | 0.2 | 1.22 | Ambiguous | 1.43 | Ambiguous | 0.29 | Likely Benign | -6.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.83 | Pathogenic | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.349A>T | S117C 2D AIThe SynGAP1 missense variant S117C 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, 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 protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -5.980 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.246 | Likely Benign | 0.1222 | 0.5057 | -1.81 | Neutral | 0.992 | Probably Damaging | 0.667 | Possibly Damaging | 3.68 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.895C>A | R299S 2D 3DClick to see structure in 3D Viewer AISynGAP1 R299S is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from REVEL and SIFT, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is inconclusive, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Overall, the evidence points to a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.276 | In-Between | 0.882 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.2780 | 0.5057 | 2.86 | Destabilizing | 0.3 | 1.46 | Ambiguous | 2.16 | Destabilizing | 1.07 | Destabilizing | -3.20 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.07 | Tolerated | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.2776T>C | S926P 2D AIThe SynGAP1 missense variant S926P is not 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 outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), yielding a Likely Pathogenic classification. AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S926P. 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -3.873 | Likely Benign | 0.916 | Likely Pathogenic | Ambiguous | 0.424 | Likely Benign | 0.1738 | 0.5058 | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3935C>G | A1312G 2D AIThe SynGAP1 missense variant A1312G is not 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 the variant being 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 | 0.767246 | Disordered | 0.971112 | Binding | 0.392 | 0.902 | 0.750 | -3.735 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.157 | Likely Benign | 0.2241 | 0.5058 | -2.25 | Neutral | 0.978 | Probably Damaging | 0.983 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2201C>T | P734L 2D AIThe SynGAP1 missense variant P734L is reported in gnomAD (variant ID 6‑33441666‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | 6-33441666-C-T | 3 | 1.86e-6 | -3.472 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 0.2390 | 0.5059 | -2.11 | Neutral | 0.897 | Possibly Damaging | 0.330 | Benign | 2.69 | Benign | 1.00 | Tolerated | 3.64 | 6 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| 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 | 0.1240 | 0.5060 | -2.07 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.55 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.2291A>G | N764S 2D  AIThe SynGAP1 missense variant N764S is listed in ClinVar as Benign (ClinVar ID 1948460.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, consistent with the ClinVar classification, and there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | Benign | 1 | -3.149 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.3762 | 0.5062 | -0.84 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.61 | Tolerated | 3.64 | 6 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||
| c.3311C>A | P1104Q 2D AIThe SynGAP1 missense variant P1104Q is reported in gnomAD (ID 6‑33443863‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, 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 | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | 6-33443863-C-A | -3.161 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.114 | Likely Benign | 0.1498 | 0.5063 | -0.64 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 3.77 | 5 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.610T>A | S204T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic effect. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors classify S204T as benign, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -4.164 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.0857 | 0.5063 | 0.75 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.97 | Ambiguous | -0.52 | Ambiguous | 0.55 | Neutral | 0.462 | Possibly Damaging | 0.173 | Benign | 4.19 | Benign | 1.00 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1600T>A | S534T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Thus, the overall evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.925 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.200 | Likely Benign | 0.1238 | 0.5064 | 0.10 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.28 | Likely Benign | 0.19 | Likely Benign | -2.42 | Neutral | 0.676 | Possibly Damaging | 0.933 | Probably Damaging | 3.32 | Benign | 0.07 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.2236G>C | V746L 2D AIThe SynGAP1 missense variant V746L is catalogued in gnomAD (ID 6‑33441701‑G‑C) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized 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. Taken together, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | 6-33441701-G-C | 1 | 6.19e-7 | -3.260 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.015 | Likely Benign | 0.0896 | 0.5065 | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.2236G>T | V746L 2D AIThe SynGAP1 missense variant V746L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that V746L 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -3.260 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.015 | Likely Benign | 0.0896 | 0.5065 | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||
| c.575C>T | A192V 2D AIThe SynGAP1 missense variant A192V is not 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, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority (2 pathogenic vs. 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that A192V 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. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.464 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | 0.0904 | 0.5066 | -2.66 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.01 | Benign | 0.11 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.59C>A | P20H 2D AIThe SynGAP1 missense variant P20H is reported in gnomAD (ID 6‑33420323‑C‑A) but has no ClinVar entry. Functional 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, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates benign. Foldetta results are unavailable. Overall, the preponderance of evidence from both consensus and high‑accuracy tools points to a benign effect for P20H, and this conclusion does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | 6-33420323-C-A | -4.450 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.132 | Likely Benign | 0.1834 | 0.5066 | -0.69 | Neutral | 0.992 | Probably Damaging | 0.893 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.720C>A | D240E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D240E missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated predictors (seven pathogenic vs. four benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current computational evidence, 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 | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.713 | Likely Pathogenic | 0.1155 | 0.5066 | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.720C>G | D240E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D240E is a missense change in the PH domain. No ClinVar entry exists for this variant, and it is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, FoldX, premPS, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—AlphaMissense‑Optimized, Rosetta, and Foldetta—are treated as unavailable. High‑accuracy assessments show the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide no definitive verdict. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.713 | Likely Pathogenic | 0.1155 | 0.5066 | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1288A>C | M430L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Rosetta, PolyPhen‑2 (HumDiv and HumVar), SIFT, and REVEL; no tool predicts pathogenicity. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all available evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -5.873 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.1767 | 0.5067 | 0.33 | Likely Benign | 0.1 | -0.10 | Likely Benign | 0.12 | Likely Benign | 0.72 | Ambiguous | -1.07 | Neutral | 0.028 | Benign | 0.004 | Benign | 3.69 | Benign | 0.66 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1288A>T | M430L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Rosetta, PolyPhen‑2 (HumDiv and HumVar), SIFT, and REVEL; no tool predicts pathogenicity. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all available evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -5.873 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.1767 | 0.5067 | 0.33 | Likely Benign | 0.1 | -0.10 | Likely Benign | 0.12 | Likely Benign | 0.72 | Ambiguous | -1.07 | Neutral | 0.028 | Benign | 0.004 | Benign | 3.69 | Benign | 0.66 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.765C>A | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change D255E 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 premPS, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions (seven pathogenic vs. four benign) point to a likely pathogenic impact. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.508 | Likely Pathogenic | 0.1365 | 0.5067 | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.765C>G | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255E 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 premPS, SIFT, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tools (FoldX, Rosetta, Foldetta) provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta is also inconclusive. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.509 | Likely Pathogenic | 0.1365 | 0.5067 | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.83C>A | S28Y 2D AIThe SynGAP1 missense variant S28Y is not 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 unavailable. Overall, the majority of evidence points to a benign effect. There is no conflict with 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 | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.521 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.0895 | 0.5067 | -0.94 | Neutral | 0.009 | Benign | 0.001 | Benign | 4.13 | Benign | 0.05 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.955G>C | A319P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319P is catalogued in gnomAD (ID 6‑33437860‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive are Rosetta, ESM1b, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | 6-33437860-G-C | 3 | 1.86e-6 | -7.213 | In-Between | 0.109 | Likely Benign | Likely Benign | 0.286 | Likely Benign | 0.1839 | 0.5067 | -0.02 | Likely Benign | 0.9 | -1.18 | Ambiguous | -0.60 | Ambiguous | 0.22 | Likely Benign | 0.11 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.97 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||
| 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 | 0.0933 | 0.5069 | -1.71 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.64 | Benign | 0.09 | Tolerated | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3146C>A | P1049H 2D AIThe SynGAP1 missense variant P1049H 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 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.427 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.1800 | 0.5070 | -2.06 | Neutral | 0.978 | Probably Damaging | 0.750 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.157G>T | G53W 2D  AIThe SynGAP1 missense variant G53W is not 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, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of available predictions (six pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -11.012 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.243 | Likely Benign | 0.0678 | 0.5071 | -1.69 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 4.08 | Benign | 0.00 | Affected | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| c.3205C>A | Q1069K 2D AIThe SynGAP1 missense variant Q1069K is not 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 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 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 points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -5.080 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.099 | Likely Benign | 0.1904 | 0.5071 | -0.88 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.77 | Benign | 0.28 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3761A>G | E1254G 2D AIThe SynGAP1 missense variant E1254G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized indicates a benign change, but the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the SGM Consensus suggests that the variant is most likely pathogenic, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -10.156 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 0.315 | Likely Benign | 0.2636 | 0.5072 | -4.52 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.34 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.3815A>G | E1272G 2D AIThe SynGAP1 missense variant E1272G is catalogued in gnomAD (ID 6‑33447863‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. The high‑accuracy AlphaMissense‑Optimized assessment is uncertain, and the Foldetta protein‑folding stability analysis is not available for this residue. Overall, the majority of evidence points toward a deleterious effect, so the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for E1272G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447863-A-G | -1.919 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.287 | Likely Benign | 0.2804 | 0.5072 | -5.89 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||
| c.154T>G | S52A 2D AIThe SynGAP1 missense variant S52A 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; the only tool predicting a pathogenic outcome is SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise 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 available predictions strongly supports 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 | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.326 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.5389 | 0.5073 | Strenghten | -0.69 | Neutral | 0.140 | Benign | 0.355 | Benign | 4.17 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.1601C>A | S534Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus six) lean toward a pathogenic effect, and the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -11.540 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.314 | Likely Benign | 0.0629 | 0.5073 | -0.01 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.46 | Likely Benign | -5.02 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.2252C>A | P751Q 2D AIThe SynGAP1 missense variant P751Q 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 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -5.273 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.1488 | 0.5073 | -2.07 | Neutral | 0.837 | Possibly Damaging | 0.531 | Possibly Damaging | 2.68 | Benign | 0.05 | Affected | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.284A>T | H95L 2D AIThe SynGAP1 missense variant H95L is not 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 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 | 0.661982 | Disordered | 0.590542 | Binding | 0.335 | 0.875 | 0.625 | -1.967 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.085 | Likely Benign | 0.1017 | 0.5074 | -2.31 | Neutral | 0.084 | Benign | 0.007 | Benign | 4.17 | Benign | 0.00 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.436T>A | S146T 2D AIThe SynGAP1 missense variant S146T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a tie (two pathogenic, two benign) and thus unavailable; Foldetta results are not provided. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -9.795 | Likely Pathogenic | 0.786 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | 0.1267 | 0.5075 | -2.09 | Neutral | 0.084 | Benign | 0.042 | Benign | 3.65 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.1346G>C | S449T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on these predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -6.262 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.1219 | 0.5077 | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1382C>T | A461V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Because the majority of standard predictors (nine benign vs. three pathogenic) favor a benign outcome, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -9.968 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | 0.141 | Likely Benign | 0.0819 | 0.5078 | -0.08 | Likely Benign | 0.3 | 0.34 | Likely Benign | 0.13 | Likely Benign | 0.02 | Likely Benign | -3.05 | Deleterious | 0.983 | Probably Damaging | 0.273 | Benign | 3.43 | Benign | 0.66 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| c.581A>C | E194A 2D AIThe SynGAP1 missense variant E194A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions—including the high‑accuracy tools—suggest that E194A is 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. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -7.101 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.235 | Likely Benign | 0.4331 | 0.5079 | -3.75 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.99 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.671C>A | T224N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact. This conclusion 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. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -7.342 | In-Between | 0.814 | Likely Pathogenic | Ambiguous | 0.370 | Likely Benign | 0.1460 | 0.5079 | 0.66 | Ambiguous | 0.2 | -0.06 | Likely Benign | 0.30 | Likely Benign | 1.15 | Destabilizing | -2.40 | Neutral | 0.845 | Possibly Damaging | 0.368 | Benign | 5.54 | Benign | 0.34 | Tolerated | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||
| c.2221C>A | P741T 2D AIThe SynGAP1 missense variant P741T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.626 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.1209 | 0.5080 | -0.54 | Neutral | 0.010 | Benign | 0.022 | Benign | 2.86 | Benign | 0.05 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.34A>G | S12G 2D AIThe SynGAP1 missense variant S12G is reported in gnomAD (ID 6‑33420298‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for S12G, 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 | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | 6-33420298-A-G | -4.229 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.2876 | 0.5080 | 0.22 | Neutral | 0.103 | Benign | 0.015 | Benign | 4.11 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||
| c.3826G>T | D1276Y 2D AIThe SynGAP1 missense variant D1276Y is catalogued in gnomAD (ID 6‑33447874‑G‑T) but has no ClinVar entry. Functional prediction tools fall 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 show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic effect; Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar status, as none is currently reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 6-33447874-G-T | -1.558 | Likely Benign | 0.768 | Likely Pathogenic | Likely Benign | 0.325 | Likely Benign | 0.0385 | 0.5082 | -6.66 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 1.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -4 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||
| c.3145C>T | P1049S 2D AIThe SynGAP1 missense variant P1049S is reported in gnomAD (variant ID 6‑33443697‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, 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. No Foldetta stability data are available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, indicate that P1049S 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | 6-33443697-C-T | 2 | 1.24e-6 | -2.351 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.3144 | 0.5083 | -1.53 | Neutral | 0.519 | Possibly Damaging | 0.303 | Benign | 2.76 | Benign | 0.04 | Affected | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.1190G>A | C397Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397Y is not 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the combined Foldetta method. Uncertain results come from AlphaMissense‑Default and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of tools and the high‑accuracy consensus lean toward a benign interpretation, and this does not contradict any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -7.213 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.455 | Likely Benign | 0.1299 | 0.5084 | 2.01 | Destabilizing | 2.3 | 8.64 | Destabilizing | 5.33 | Destabilizing | 0.12 | Likely Benign | -1.82 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.64 | Benign | 0.07 | Tolerated | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||
| c.3212G>C | G1071A 2D AIThe SynGAP1 missense variant G1071A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -1.825 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.3376 | 0.5084 | -1.34 | Neutral | 0.025 | Benign | 0.022 | Benign | 4.12 | Benign | 0.05 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1108G>A | G370S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G370S is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438013‑G‑A). Consensus predictions from standard in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, FATHMM). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | Uncertain | 1 | 6-33438013-G-A | 15 | 9.31e-6 | -3.533 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.282 | Likely Benign | 0.2664 | 0.5086 | 2.83 | Destabilizing | 2.0 | 1.05 | Ambiguous | 1.94 | Ambiguous | -0.02 | Likely Benign | 0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.77 | Tolerated | 3.42 | 19 | 1 | 0 | -0.4 | 30.03 | 196.6 | -49.6 | 0.9 | 2.2 | -0.1 | 0.4 | Uncertain | Gly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn. | ||||||||||
| c.2335A>G | S779G 2D AIThe SynGAP1 missense variant S779G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.304 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.2894 | 0.5087 | 0.38 | Neutral | 0.393 | Benign | 0.324 | Benign | 2.65 | Benign | 0.53 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.2683A>G | S895G 2D AIThe SynGAP1 missense variant S895G is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -3.728 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.2675 | 0.5087 | -1.25 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.67 | Benign | 0.90 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3451T>G | S1151A 2D AIThe SynGAP1 missense variant S1151A 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” consensus. High‑accuracy assessments further support a benign classification: 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 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.311 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.4711 | 0.5087 | -0.13 | Neutral | 0.889 | Possibly Damaging | 0.535 | Possibly Damaging | 2.75 | Benign | 0.42 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.2622G>C | Q874H 2D  AIThe SynGAP1 missense variant Q874H is not 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 further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the balance of evidence from both general and high‑accuracy predictors indicates that 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. | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -4.658 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.236 | Likely Benign | 0.1588 | 0.5088 | -2.90 | Deleterious | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.2622G>T | Q874H 2D AIThe SynGAP1 missense variant Q874H has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority, and Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -4.658 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.236 | Likely Benign | 0.1588 | 0.5088 | -2.90 | Deleterious | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3005A>T | H1002L 2D AIThe SynGAP1 H1002L 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 and the absence of the variant in population databases, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -6.448 | Likely Benign | 0.556 | Ambiguous | Likely Benign | 0.157 | Likely Benign | 0.1296 | 0.5088 | -3.12 | Deleterious | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.79 | Benign | 0.13 | Tolerated | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.2447 | 0.5089 | -1.10 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 2.62 | Benign | 0.65 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2324G>T | R775L 2D AIThe SynGAP1 missense variant R775L is listed in gnomAD (ID 6‑33442482‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic 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 | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | 6-33442482-G-T | -5.951 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | 0.1665 | 0.5089 | -1.86 | Neutral | 0.933 | Possibly Damaging | 0.871 | Possibly Damaging | 4.13 | Benign | 0.06 | Tolerated | 3.64 | 6 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||
| c.1949A>G | N650S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650S lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results come from AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, and premPS. For high‑accuracy methods, AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the majority of available predictions support a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -11.291 | Likely Pathogenic | 0.916 | Likely Pathogenic | Ambiguous | 0.395 | Likely Benign | 0.3791 | 0.5090 | 0.79 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.11 | Ambiguous | 0.77 | Ambiguous | -4.98 | Deleterious | 0.996 | Probably Damaging | 0.606 | Possibly Damaging | 3.06 | Benign | 0.02 | Affected | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.1191C>G | C397W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus, whereas pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, but Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Overall, the majority of tools lean toward a benign effect, and this is consistent with the lack of ClinVar evidence. Therefore, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -6.857 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 0.545 | Likely Pathogenic | 0.1637 | 0.5092 | 2.40 | Destabilizing | 2.3 | 4.46 | Destabilizing | 3.43 | Destabilizing | 0.19 | Likely Benign | -1.87 | Neutral | 0.987 | Probably Damaging | 0.814 | Possibly Damaging | 4.64 | Benign | 0.02 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.2900G>T | R967L 2D AIThe SynGAP1 missense variant R967L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443452‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for R967L, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.974374 | Disordered | 0.969686 | Binding | 0.340 | 0.888 | 0.750 | Uncertain | 1 | 6-33443452-G-T | 1 | 6.20e-7 | -3.496 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.123 | Likely Benign | 0.1964 | 0.5093 | -0.99 | Neutral | 0.959 | Probably Damaging | 0.586 | Possibly Damaging | 4.15 | Benign | 0.75 | Tolerated | 4.32 | 2 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||
| c.4013G>C | R1338P 2D AISynGAP1 missense variant R1338P 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 a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the available predictions are evenly split between benign and pathogenic, with no high‑accuracy tool providing definitive support. Therefore, the variant is most likely pathogenic based on the balance of evidence, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.977425 | Binding | 0.393 | 0.697 | 1.000 | -3.678 | Likely Benign | 0.954 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | 0.2065 | 0.5095 | -3.43 | Deleterious | 0.931 | Possibly Damaging | 0.410 | Benign | 3.75 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||
| c.1522G>C | D508H 2D  AISynGAP1 D508H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show an even split: benign calls come from REVEL, FoldX, premPS, SIFT, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain outcome from AlphaMissense‑Optimized, and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.074 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.336 | Likely Benign | 0.1804 | 0.5096 | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.2906G>C | G969A 2D AIThe SynGAP1 missense variant G969A is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments corroborate this benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are not available, so they do not influence the interpretation. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.693 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.120 | Likely Benign | 0.3414 | 0.5096 | -0.36 | Neutral | 0.393 | Benign | 0.096 | Benign | 4.25 | Benign | 0.51 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1171G>A | G391S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391S 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and FoldX. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact for G391S, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -5.531 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.462 | Likely Benign | 0.2820 | 0.5097 | 2.14 | Destabilizing | 0.6 | 1.01 | Ambiguous | 1.58 | Ambiguous | 0.06 | Likely Benign | -0.54 | Neutral | 0.978 | Probably Damaging | 0.777 | Possibly Damaging | 1.33 | Pathogenic | 0.35 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.925G>C | G309R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. Uncertainty remains for FoldX, Rosetta, Foldetta, and premPS, which are listed as uncertain and do not influence the overall assessment. High‑accuracy evaluations show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -14.375 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 0.0964 | 0.5097 | 1.99 | Ambiguous | 0.5 | 0.52 | Ambiguous | 1.26 | Ambiguous | 0.55 | Ambiguous | -7.35 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.3602A>G | E1201G 2D AIThe SynGAP1 missense variant E1201G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction comes from REVEL, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify it as pathogenic. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) confirms pathogenicity. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the preponderance of evidence points to the variant being most likely pathogenic, 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 Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -13.190 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | 0.2632 | 0.5099 | -5.31 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.461G>C | S154T 2D AIThe SynGAP1 missense variant S154T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -5.313 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.1686 | 0.5099 | -0.32 | Neutral | 0.900 | Possibly Damaging | 0.434 | Benign | 4.13 | Benign | 0.99 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1112G>A | S371N 2D AIThe SynGAP1 missense variant S371N is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments are consistent: AlphaMissense‑Optimized classifies the variant as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -5.950 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.208 | Likely Benign | 0.2068 | 0.5100 | 0.21 | Likely Benign | 0.8 | -0.59 | Ambiguous | -0.19 | Likely Benign | 0.25 | Likely Benign | -0.31 | Neutral | 0.666 | Possibly Damaging | 0.067 | Benign | 4.64 | Benign | 0.27 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||
| 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 | 0.2031 | 0.5101 | -3.22 | Deleterious | 0.007 | Benign | 0.006 | Benign | 2.44 | Pathogenic | 0.08 | Tolerated | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||
| c.4008G>C | E1336D 2D AIThe SynGAP1 missense variant E1336D is listed in ClinVar (ID 3323942.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a 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, consistent with the ClinVar benign 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 | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | Likely Benign | 1 | -3.344 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.062 | Likely Benign | 0.1995 | 0.5101 | -1.92 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.30 | Benign | 0.00 | Affected | 3.77 | 5 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||
| c.4008G>T | E1336D 2D AIThe SynGAP1 missense variant E1336D is catalogued in gnomAD (ID 6‑33451882‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. Only two tools—SIFT and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also reports it as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence 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 | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | 6-33451882-G-T | -3.344 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | 0.1995 | 0.5101 | -1.92 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.30 | Benign | 0.00 | Affected | 3.77 | 5 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||
| c.2446T>C | S816P 2D AIThe SynGAP1 missense variant S816P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are unavailable. Overall, the preponderance of evidence points to a benign effect for S816P, and this conclusion is not in conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.662 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.160 | Likely Benign | 0.2298 | 0.5102 | -0.26 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.66 | Benign | 0.45 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0598 | 0.5103 | -3.35 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.1298C>T | A433V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A433V missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438203‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, 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 and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable as evidence. Overall, the majority of predictions support a benign impact, and this is consistent with the lack of ClinVar pathogenic classification. 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. | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | 6-33438203-C-T | 240 | 1.49e-4 | -8.200 | Likely Pathogenic | 0.129 | Likely Benign | Likely Benign | 0.096 | Likely Benign | 0.0753 | 0.5104 | 0.48 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.21 | Likely Benign | 0.48 | Likely Benign | -2.91 | Deleterious | 0.994 | Probably Damaging | 0.527 | Possibly Damaging | 3.43 | Benign | 0.04 | Affected | 3.37 | 29 | 0 | 0 | 2.4 | 28.05 | 214.5 | -45.8 | 0.0 | 0.0 | 0.0 | 0.2 | X | Potentially Benign | The methyl group of Ala433, located on the outer surface of an α helix (res. Met414-Glu436), does not interact with any nearby residues in the WT simulations. In the variant simulations, the iso-propyl side chain of Val433, which has a similarly hydrophobic profile as alanine, also does not form any lasting interactions at the helix surface. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | ||||||||||||
| c.3466G>C | A1156P 2D AIThe SynGAP1 missense variant A1156P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A1156P is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -2.847 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.405 | Likely Benign | 0.1718 | 0.5104 | -3.49 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.2144C>T | P715L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Because the majority of consensus and individual predictors indicate pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for P715L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.207 | Likely Pathogenic | 0.764 | Likely Pathogenic | Likely Benign | 0.318 | Likely Benign | 0.1944 | 0.5105 | 1.43 | Ambiguous | 0.1 | 0.06 | Likely Benign | 0.75 | Ambiguous | 0.58 | Ambiguous | -9.10 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.2992G>C | A998P 2D AIThe SynGAP1 missense variant A998P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for A998P. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -2.220 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.171 | Likely Benign | 0.1924 | 0.5106 | -0.40 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.682A>T | T228S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. Taken together, the overwhelming majority of evidence indicates a benign impact for T228S. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -2.028 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.458 | Likely Benign | 0.3395 | 0.5107 | 0.32 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.48 | Likely Benign | 0.05 | Likely Benign | -0.50 | Neutral | 0.734 | Possibly Damaging | 0.138 | Benign | 5.65 | Benign | 1.00 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| 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 | 0.2504 | 0.5108 | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 2.63 | Benign | 0.10 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.2858C>A | P953Q 2D AIThe SynGAP1 missense variant P953Q is listed in ClinVar with an uncertain significance (ClinVar ID 1176820.0) and is not found in gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments corroborate this: 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 all available predictions points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | Uncertain | 1 | -6.038 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 0.2105 | 0.5108 | -0.78 | Neutral | 0.058 | Benign | 0.015 | Benign | 2.78 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||
| 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 | 0.2077 | 0.5109 | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||
| 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 | 0.2288 | 0.5109 | -2.48 | Neutral | 0.969 | Probably Damaging | 0.659 | Possibly Damaging | 2.43 | Pathogenic | 0.02 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.524A>T | Q175L 2D AIThe SynGAP1 missense variant Q175L is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 (2 vs 2), and Foldetta results are unavailable. Overall, seven tools favor benign while two favor pathogenic, with no ClinVar evidence to contradict this. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -8.699 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | 0.0647 | 0.5109 | -2.46 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.10 | Benign | 0.14 | Tolerated | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||
| c.3349G>A | G1117S 2D AIThe SynGAP1 missense variant G1117S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -3.890 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.211 | Likely Benign | 0.2572 | 0.5111 | -0.37 | Neutral | 0.032 | Benign | 0.026 | Benign | 5.08 | Benign | 0.17 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3364G>A | G1122S 2D AIThe SynGAP1 missense variant G1122S is listed in ClinVar as a benign alteration (ClinVar ID 643187.0) and is present in gnomAD (gnomAD ID 6‑33443916‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely benign, while Foldetta’s protein‑folding stability result is unavailable. Overall, the variant is most likely benign, and this assessment is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | Benign/Likely benign | 2 | 6-33443916-G-A | 27 | 1.79e-5 | -4.880 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.189 | Likely Benign | 0.2537 | 0.5111 | -0.08 | Neutral | 0.022 | Benign | 0.006 | Benign | 4.89 | Benign | 0.92 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||
| c.3367G>A | G1123S 2D AIThe SynGAP1 missense variant G1123S is reported in gnomAD (variant ID 6-33443919-G-A) but has no ClinVar entry. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | 6-33443919-G-A | -4.918 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.291 | Likely Benign | 0.2554 | 0.5111 | -0.32 | Neutral | 0.292 | Benign | 0.157 | Benign | 4.66 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| 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 | 0.1807 | 0.5111 | -2.06 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.14 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.2326G>C | G776R 2D AIThe SynGAP1 missense variant G776R is not 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the Foldetta protein‑folding stability assessment is unavailable for this variant. Overall, the balance of evidence leans toward a benign interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -6.209 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | 0.0932 | 0.5115 | -2.28 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 4.22 | Benign | 0.01 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.1307A>C | E436A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436A is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, and FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. Two high‑accuracy predictors give concordant results: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. No prediction is missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for E436A, 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 | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.678 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.825 | Likely Pathogenic | 0.3901 | 0.5116 | 1.03 | Ambiguous | 0.0 | -0.88 | Ambiguous | 0.08 | Likely Benign | 0.23 | Likely Benign | -5.68 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 4.65 | Benign | 0.05 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.2572A>G | S858G 2D AIThe SynGAP1 missense variant S858G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumVar indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -2.181 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.143 | Likely Benign | 0.3084 | 0.5116 | -0.18 | Neutral | 0.259 | Benign | 0.786 | Possibly Damaging | 4.13 | Benign | 0.11 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.1060G>T | A354S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A354S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence indicates that A354S is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.203355 | Structured | 0.381329 | Uncertain | 0.882 | 0.335 | 0.125 | -3.005 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.2829 | 0.5117 | 0.02 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.15 | Likely Benign | -0.10 | Likely Benign | 0.28 | Neutral | 0.005 | Benign | 0.001 | Benign | 1.76 | Pathogenic | 0.21 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1400A>C | D467A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467A 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 and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results—FoldX, Rosetta, and Foldetta—do not provide decisive evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.499 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.790 | Likely Pathogenic | 0.3134 | 0.5117 | 0.83 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.23 | Likely Benign | -7.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.19 | Pathogenic | 0.07 | Tolerated | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| 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 | 0.2069 | 0.5117 | -2.36 | Neutral | 0.770 | Possibly Damaging | 0.242 | Benign | 2.47 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||
| c.418T>C | S140P 2D AIThe SynGAP1 missense variant S140P is not 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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. High‑accuracy tools specifically show AlphaMissense‑Optimized as pathogenic, while SGM Consensus and Foldetta are unavailable. Overall, the majority of evidence points to a pathogenic impact for S140P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -4.089 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | 0.1726 | 0.5117 | -2.59 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.52 | Benign | 0.08 | Tolerated | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||
| c.1733A>C | E578A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E578A missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta also predicts benign. Overall, the majority of conventional tools lean benign, but the high‑accuracy consensus and AlphaMissense‑Optimized suggest a pathogenic effect. Thus, the variant is most likely pathogenic according to the most reliable predictors, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.059222 | Structured | 0.020971 | Uncertain | 0.902 | 0.240 | 0.000 | -7.369 | In-Between | 0.604 | Likely Pathogenic | Likely Benign | 0.525 | Likely Pathogenic | 0.3326 | 0.5118 | 0.34 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.07 | Likely Benign | -0.02 | Likely Benign | -2.30 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.40 | Pathogenic | 0.44 | Tolerated | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||
| c.1690G>C | E564Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E564Q is not reported in ClinVar and has no gnomAD entry. Consensus from standard predictors shows a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and SIFT, while pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta predicts benign stability. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus supports this view. The variant is therefore most likely pathogenic, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | -12.077 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.598 | Likely Pathogenic | 0.0982 | 0.5119 | 0.33 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.30 | Likely Benign | -0.03 | Likely Benign | -2.95 | Deleterious | 0.996 | Probably Damaging | 0.986 | Probably Damaging | -1.26 | Pathogenic | 0.12 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| 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 | 0.2379 | 0.5121 | -0.59 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.51 | Benign | 0.11 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.2749C>T | P917S 2D AIThe SynGAP1 missense variant P917S is catalogued in gnomAD (ID 6‑33443301‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. Only SIFT predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so it provides no additional evidence. Overall, the preponderance of predictions indicates that P917S 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 | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | 6-33443301-C-T | 1 | 6.20e-7 | -3.562 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.056 | Likely Benign | 0.3478 | 0.5121 | -0.54 | Neutral | 0.003 | Benign | 0.002 | Benign | 2.70 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3409C>T | H1137Y 2D AIThe SynGAP1 missense variant H1137Y 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 H1137Y, 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 | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -4.506 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.310 | Likely Benign | 0.1073 | 0.5123 | -1.93 | Neutral | 0.925 | Possibly Damaging | 0.629 | Possibly Damaging | 5.28 | Benign | 0.00 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.461G>T | S154I 2D AIThe SynGAP1 missense variant S154I is not 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, 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, was not provided and is treated as unavailable. High‑accuracy predictions therefore indicate a benign outcome (AlphaMissense‑Optimized) with no decisive evidence from SGM Consensus or Foldetta. Overall, the variant is most likely benign, 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. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -10.061 | Likely Pathogenic | 0.665 | Likely Pathogenic | Likely Benign | 0.105 | Likely Benign | 0.0953 | 0.5123 | -2.24 | Neutral | 0.990 | Probably Damaging | 0.797 | Possibly Damaging | 4.03 | Benign | 0.07 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.0715 | 0.5124 | -3.07 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.55 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.1758C>A | D586E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -3.233 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | 0.367 | Likely Benign | 0.1304 | 0.5126 | -0.42 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.23 | Likely Benign | 0.38 | Likely Benign | -0.12 | Neutral | 0.929 | Possibly Damaging | 0.969 | Probably Damaging | -1.20 | Pathogenic | 1.00 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.1758C>G | D586E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -3.233 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | 0.367 | Likely Benign | 0.1304 | 0.5126 | -0.42 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.23 | Likely Benign | 0.38 | Likely Benign | -0.12 | Neutral | 0.929 | Possibly Damaging | 0.969 | Probably Damaging | -1.20 | Pathogenic | 1.00 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.3809A>C | E1270A 2D AIThe SynGAP1 missense change E1270A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL is the only score that flags the variant as benign, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect, and the SGM‑Consensus also indicates a likely pathogenic outcome. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a pathogenic impact for E1270A, and this conclusion is consistent with the absence of a ClinVar entry (i.e., no contradictory clinical classification). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -12.081 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.388 | Likely Benign | 0.3024 | 0.5126 | -5.04 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||
| c.1264G>A | E422K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E422K missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the balance of evidence leans toward pathogenicity, and this assessment 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. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -13.042 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.346 | Likely Benign | 0.1995 | 0.5129 | 0.30 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.20 | Likely Benign | 0.32 | Likely Benign | -3.52 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.39 | Benign | 0.04 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.2554G>A | G852S 2D AIThe SynGAP1 missense variant G852S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -4.786 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.2696 | 0.5129 | -0.17 | Neutral | 0.393 | Benign | 0.197 | Benign | 4.21 | Benign | 0.07 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3037T>G | S1013A 2D AIThe SynGAP1 missense variant S1013A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -3.400 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.4728 | 0.5131 | -0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.71 | Benign | 0.30 | Tolerated | 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 | 0.1817 | 0.5132 | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 4.32 | 4 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||
| c.2540A>T | Q847L 2D AIThe SynGAP1 missense variant Q847L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default—predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely 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 lean toward pathogenicity, and this conclusion does not contradict any existing ClinVar annotation, as 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 | 0.653063 | Disordered | 0.577677 | Binding | 0.282 | 0.818 | 0.500 | -6.966 | Likely Benign | 0.625 | Likely Pathogenic | Likely Benign | 0.326 | Likely Benign | 0.0701 | 0.5132 | -4.52 | Deleterious | 0.818 | Possibly Damaging | 0.637 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.2836G>A | G946R 2D AIThe SynGAP1 missense variant G946R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. 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 Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | 0.1157 | 0.5133 | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2836G>C | G946R 2D AIThe SynGAP1 missense variant G946R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. 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 Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | 0.1157 | 0.5133 | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2918G>C | G973A 2D AIThe SynGAP1 missense variant G973A is reported in gnomAD (ID 6‑33443470‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | 6-33443470-G-C | 1 | 6.20e-7 | -3.847 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.3405 | 0.5133 | 0.14 | Neutral | 0.112 | Benign | 0.028 | Benign | 4.30 | Benign | 0.62 | Tolerated | 4.32 | 2 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.3149G>C | G1050A 2D AIThe SynGAP1 missense variant G1050A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -5.514 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 0.3349 | 0.5133 | 0.18 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.68 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3182G>C | G1061A 2D AIThe SynGAP1 missense variant G1061A is not 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 unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -6.328 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.3289 | 0.5133 | -0.34 | Neutral | 0.004 | Benign | 0.002 | Benign | 4.01 | Benign | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3187G>C | G1063R 2D AIThe SynGAP1 missense variant G1063R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The 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 collective evidence strongly supports 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 | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -5.711 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.078 | Likely Benign | 0.1037 | 0.5133 | 0.55 | Neutral | 0.411 | Benign | 0.114 | Benign | 4.28 | Benign | 0.09 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2625 | 0.5134 | -1.23 | Neutral | 0.942 | Possibly Damaging | 0.788 | Possibly Damaging | 2.63 | Benign | 0.04 | Affected | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.496G>A | A166T 2D AIThe SynGAP1 missense variant A166T 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, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.700 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.115 | Likely Benign | 0.1420 | 0.5134 | -0.78 | Neutral | 0.399 | Benign | 0.273 | Benign | 4.10 | Benign | 0.31 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3421C>G | P1141A 2D AIThe SynGAP1 missense variant P1141A is not 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, 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, a protein‑folding‑stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore provide mixed evidence: AlphaMissense‑Optimized indicates benign, while the consensus and stability analyses are unavailable. Overall, the majority of individual predictors (five versus four) favor a pathogenic interpretation, and this does not contradict any ClinVar annotation because none exists. 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. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -3.885 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.3525 | 0.5135 | -3.67 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 1.00 | Pathogenic | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1613 | 0.5136 | -1.10 | Neutral | 0.918 | Possibly Damaging | 0.604 | Possibly Damaging | 2.58 | Benign | 0.12 | Tolerated | 3.77 | 5 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.2002T>C | S668P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668P has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the only benign predictor, while the remaining 13 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 or likely pathogenic. The premPS score is uncertain and therefore not used as evidence. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -13.452 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.612 | Likely Pathogenic | 0.1979 | 0.5137 | 6.40 | Destabilizing | 1.1 | 10.90 | Destabilizing | 8.65 | Destabilizing | 0.61 | Ambiguous | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.16 | Benign | 0.02 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.383C>T | P128L 2D AIThe SynGAP1 missense variant P128L is catalogued in gnomAD (6‑33432248‑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). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is reported). 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 | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | 6-33432248-C-T | 1 | 6.20e-7 | -4.791 | Likely Benign | 0.541 | Ambiguous | Likely Benign | 0.087 | Likely Benign | 0.2548 | 0.5137 | -0.47 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.20 | Benign | 0.38 | Tolerated | 3.74 | 4 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.1214G>C | R405P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405P is listed in ClinVar with an “Uncertain” status 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies it as pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Uncertain | 1 | -14.206 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 0.2140 | 0.5138 | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||
| c.196C>G | P66A 2D AIThe SynGAP1 P66A missense variant (ClinVar ID 1303518.0) is listed as “Uncertain” and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. Separately, the high‑accuracy AlphaMissense‑Optimized result is “Uncertain,” the SGM‑Consensus remains “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the predictions are mixed, but the majority of high‑confidence tools lean toward a benign effect. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | Uncertain | 1 | -2.845 | Likely Benign | 0.891 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.3467 | 0.5138 | -1.56 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||
| 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 | 0.3301 | 0.5138 | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3371G>C | G1124A 2D AIThe SynGAP1 missense variant G1124A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and the Foldetta stability analysis is unavailable. Taken together, the overwhelming majority of computational evidence classifies G1124A as benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -6.608 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.199 | Likely Benign | 0.3494 | 0.5138 | -0.39 | Neutral | 0.059 | Benign | 0.041 | Benign | 4.81 | Benign | 0.02 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3374G>C | G1125A 2D AIThe SynGAP1 missense variant G1125A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33443926‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from the four high‑accuracy tools) is benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | Uncertain | 1 | 6-33443926-G-C | 1 | 6.68e-7 | -6.569 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.232 | Likely Benign | 0.3395 | 0.5138 | -0.60 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.60 | Benign | 0.11 | Tolerated | 3.77 | 5 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||
| c.2816C>T | P939L 2D AIThe SynGAP1 missense variant P939L is not 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 predictions show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, five tools predict pathogenicity versus four predicting benign, so the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.191 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.2113 | 0.5142 | -3.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1405 | 0.5142 | -1.91 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.1228A>G | S410G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -7.147 | In-Between | 0.137 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.2651 | 0.5143 | 0.58 | Ambiguous | 0.1 | 1.33 | Ambiguous | 0.96 | Ambiguous | 0.85 | Ambiguous | -2.54 | Deleterious | 0.952 | Possibly Damaging | 0.145 | Benign | 4.13 | Benign | 0.19 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||
| c.3010C>T | H1004Y 2D AIThe SynGAP1 missense variant H1004Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.196 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | 0.1175 | 0.5143 | -1.67 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.72 | Benign | 0.49 | Tolerated | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.229A>T | S77C 2D AIThe SynGAP1 missense variant S77C 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 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -5.549 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.022 | Likely Benign | 0.0954 | 0.5144 | -0.94 | Neutral | 0.953 | Possibly Damaging | 0.129 | Benign | 4.04 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3161G>C | G1054A 2D AIThe SynGAP1 missense variant G1054A is catalogued in gnomAD (ID 6‑33443713‑G‑C) but has no ClinVar entry. Across a broad panel of in‑silico predictors, every tool reports a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Based on the unanimous benign predictions and the lack of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | 6-33443713-G-C | -6.786 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.243 | Likely Benign | 0.3305 | 0.5144 | -0.05 | Neutral | 0.288 | Benign | 0.071 | Benign | 4.03 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3164G>C | G1055A 2D AIThe SynGAP1 missense variant G1055A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -6.835 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.3350 | 0.5144 | 0.15 | Neutral | 0.649 | Possibly Damaging | 0.148 | Benign | 3.30 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3173G>C | G1058A 2D AIThe SynGAP1 missense variant G1058A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -6.823 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.3288 | 0.5144 | 0.21 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.29 | Benign | 0.55 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3185G>C | G1062A 2D AIThe SynGAP1 missense variant G1062A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.124 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.350 | Likely Benign | 0.3305 | 0.5144 | 0.20 | Neutral | 0.059 | Benign | 0.028 | Benign | 4.20 | Benign | 0.51 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.3971 | 0.5145 | -0.48 | Neutral | 0.856 | Possibly Damaging | 0.554 | Possibly Damaging | 2.61 | Benign | 0.07 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.328G>C | V110L 2D AIThe SynGAP1 missense variant V110L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence overwhelmingly supports a benign impact for V110L, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -3.024 | Likely Benign | 0.357 | Ambiguous | Likely Benign | 0.058 | Likely Benign | 0.1165 | 0.5145 | -0.71 | Neutral | 0.158 | Benign | 0.025 | Benign | 4.20 | Benign | 0.50 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3293G>A | S1098N 2D AIThe SynGAP1 missense variant S1098N is listed in ClinVar (ID 864704.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443845‑G‑A). All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | Conflicting | 2 | 6-33443845-G-A | 6 | 3.89e-6 | -5.120 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.1665 | 0.5145 | -0.58 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.76 | Benign | 0.36 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||
| c.8G>C | R3T 2D  AIThe SynGAP1 missense variant R3T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -3.693 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.1809 | 0.5145 | -0.55 | Neutral | 0.208 | Benign | 0.018 | Benign | 4.01 | Benign | 0.00 | Affected | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||
| c.2737A>T | T913S 2D AIThe SynGAP1 missense variant T913S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -2.636 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.129 | Likely Benign | 0.3541 | 0.5147 | -0.74 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.80 | Benign | 0.74 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.92G>T | R31L 2D AIThe SynGAP1 missense variant R31L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict pathogenic. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically indicate benign: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta data are missing. Overall, the majority of reliable predictions lean toward a benign effect, 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 | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.147 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.149 | Likely Benign | 0.2264 | 0.5148 | -1.79 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.3973C>A | P1325T 2D AIThe SynGAP1 missense variant P1325T is reported in gnomAD (ID 6‑33451847‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for P1325T, 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 | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | 6-33451847-C-A | -5.880 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.1814 | 0.5150 | -0.14 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||
| c.1082A>C | Q361P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361P is listed in ClinVar as Pathogenic (ClinVar ID 3235087.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy methods specifically give a pathogenic verdict: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Based on the overwhelming agreement of these predictions, the variant is most likely pathogenic, which is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | Likely Pathogenic | 1 | -13.280 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.482 | Likely Benign | 0.1986 | 0.5151 | 3.12 | Destabilizing | 0.0 | 3.45 | Destabilizing | 3.29 | Destabilizing | 0.38 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.979 | Probably Damaging | 1.63 | Pathogenic | 0.05 | Affected | 3.37 | 25 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||
| c.2678A>C | Q893P 2D AIThe SynGAP1 missense variant Q893P is reported in gnomAD (ID 6‑33443230‑A‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑confidence tools, support 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 | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | 6-33443230-A-C | 1 | 6.20e-7 | -2.463 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.2271 | 0.5151 | -0.70 | Neutral | 0.802 | Possibly Damaging | 0.432 | Benign | 2.69 | Benign | 0.05 | Affected | 4.32 | 4 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||
| c.400A>T | S134C 2D AIThe SynGAP1 missense variant S134C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen2_HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of tools and the consensus prediction lean toward pathogenicity, which is not contradicted by ClinVar (no entry) but is opposed by the AlphaMissense‑Optimized benign call. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.184 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.247 | Likely Benign | 0.0767 | 0.5151 | -3.12 | Deleterious | 0.876 | Possibly Damaging | 0.417 | Benign | 3.79 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.769A>T | S257C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta) and pathogenic predictions (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar). The high‑accuracy consensus methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—each indicate a benign effect. No folding‑stability assessment is available beyond the benign Foldetta result. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar assertion. Thus, the variant is most likely benign, and this is not contradicted by ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -3.553 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.611 | Likely Pathogenic | 0.0880 | 0.5151 | 0.50 | Ambiguous | 0.4 | -0.33 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | 0.02 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.18 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1396T>A | S466T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence points to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -5.488 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.414 | Likely Benign | 0.0928 | 0.5152 | 0.30 | Likely Benign | 0.2 | -1.02 | Ambiguous | -0.36 | Likely Benign | -0.65 | Ambiguous | 1.05 | Neutral | 0.740 | Possibly Damaging | 0.872 | Possibly Damaging | -1.51 | Pathogenic | 1.00 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.580G>A | E194K 2D AIThe SynGAP1 missense variant E194K 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -13.294 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.259 | Likely Benign | 0.2231 | 0.5152 | -2.53 | Deleterious | 0.734 | Possibly Damaging | 0.321 | Benign | 4.04 | Benign | 0.01 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.526A>T | S176C 2D AIThe SynGAP1 missense variant S176C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy tools indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -9.785 | Likely Pathogenic | 0.529 | Ambiguous | Likely Benign | 0.143 | Likely Benign | 0.0823 | 0.5153 | -1.88 | Neutral | 0.983 | Probably Damaging | 0.436 | Benign | 4.02 | Benign | 0.02 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.2106 | 0.5154 | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.2903G>C | G968A 2D AIThe SynGAP1 missense variant G968A is predicted to be benign by all available in‑silico tools. Consensus predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. No tools predict pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of ClinVar evidence, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -4.721 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.3401 | 0.5154 | -0.33 | Neutral | 0.245 | Benign | 0.140 | Benign | 4.24 | Benign | 0.68 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3299G>C | G1100A 2D AIThe SynGAP1 missense variant G1100A is 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.862 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.146 | Likely Benign | 0.3442 | 0.5154 | -0.95 | Neutral | 0.943 | Possibly Damaging | 0.667 | Possibly Damaging | 2.01 | Pathogenic | 0.05 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.491G>T | R164L 2D AIThe SynGAP1 missense variant R164L is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the majority of evidence, including the SGM Consensus, points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for R164L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | -10.794 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.274 | Likely Benign | 0.2137 | 0.5154 | -3.37 | Deleterious | 0.001 | Benign | 0.003 | Benign | 3.80 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.2312C>A | S771Y 2D AIThe SynGAP1 missense variant S771Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.041 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.176 | Likely Benign | 0.0707 | 0.5155 | -2.13 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.05 | Affected | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.545C>A | S182Y 2D AIThe SynGAP1 missense variant S182Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign calls are made only by REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized indicates a pathogenic effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. A protein‑folding stability analysis with Foldetta is unavailable, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -15.951 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | 0.0656 | 0.5158 | -4.40 | Deleterious | 0.940 | Possibly Damaging | 0.564 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.785A>G | N262S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N262S is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two groups: benign predictions come from SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence is mixed, with a slight tilt toward pathogenicity because five tools predict pathogenic while four predict benign. The variant is most likely pathogenic based on the current predictions, and this assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -8.841 | Likely Pathogenic | 0.182 | Likely Benign | Likely Benign | 0.638 | Likely Pathogenic | 0.3101 | 0.5158 | 0.91 | Ambiguous | 0.2 | 0.90 | Ambiguous | 0.91 | Ambiguous | 0.69 | Ambiguous | -4.31 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.84 | Benign | 0.16 | Tolerated | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||
| c.2845G>A | G949S 2D AIThe SynGAP1 missense variant G949S is listed in ClinVar as a benign alteration (ClinVar ID 212352.0) and is present in the gnomAD database (6‑33443397‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | Benign/Likely benign | 4 | 6-33443397-G-A | 122 | 7.56e-5 | -5.693 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.321 | Likely Benign | 0.2528 | 0.5159 | 0.30 | Neutral | 0.611 | Possibly Damaging | 0.102 | Benign | 2.23 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 1 | 0 | -0.4 | 30.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||
| c.2987C>A | P996H 2D AIThe SynGAP1 missense variant P996H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -5.554 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.045 | Likely Benign | 0.1585 | 0.5160 | -1.19 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.25 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.1376G>C | G459A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G459A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled Uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain and therefore not considered evidence. Overall, the majority of reliable tools indicate a pathogenic 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 Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.684 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 0.3529 | 0.5161 | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.2986C>T | P996S 2D AIThe SynGAP1 missense variant P996S is reported in gnomAD (ID 6‑33443538‑C‑T) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the 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 is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | 6-33443538-C-T | 4 | 2.48e-6 | -4.461 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.3171 | 0.5161 | -0.58 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.30 | Benign | 0.09 | Tolerated | 4.32 | 4 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3967C>A | P1323T 2D AIThe SynGAP1 missense variant P1323T is reported in gnomAD (ID 6‑33451841‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two algorithms—polyPhen‑2 HumDiv and SIFT—suggest a damaging impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with any ClinVar classification, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451841-C-A | -6.296 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.1988 | 0.5161 | -0.37 | Neutral | 0.588 | Possibly Damaging | 0.227 | Benign | 3.95 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||
| c.1535A>C | E512A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -10.979 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.309 | Likely Benign | 0.4293 | 0.5162 | 0.45 | Likely Benign | 0.1 | 0.97 | Ambiguous | 0.71 | Ambiguous | 0.04 | Likely Benign | -5.71 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.764A>T | D255V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of available predictions points to a pathogenic effect for D255V, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.575 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.895 | Likely Pathogenic | 0.0684 | 0.5162 | 1.76 | Ambiguous | 0.2 | 1.07 | Ambiguous | 1.42 | Ambiguous | 0.16 | Likely Benign | -7.77 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||
| c.2561G>C | R854P 2D AIThe SynGAP1 missense variant R854P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R854P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.627 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.166 | Likely Benign | 0.2263 | 0.5163 | -1.02 | Neutral | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 4.06 | Benign | 0.03 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.4002C>A | N1334K 2D AIThe SynGAP1 missense variant N1334K is listed in gnomAD (ID 6‑33451876‑C‑A) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, 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, 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. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | 6-33451876-C-A | -4.875 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | 0.2355 | 0.5163 | -3.49 | Deleterious | 0.979 | Probably Damaging | 0.756 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||
| c.4002C>G | N1334K 2D AIThe SynGAP1 missense variant N1334K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 tie and therefore unavailable; Foldetta predictions are not provided. Overall, the balance of evidence favors a pathogenic effect for N1334K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -4.875 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | 0.2355 | 0.5163 | -3.49 | Deleterious | 0.979 | Probably Damaging | 0.756 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||
| c.2660C>T | P887L 2D AIThe SynGAP1 missense variant P887L is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.602269 | Binding | 0.348 | 0.925 | 0.500 | -4.008 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.1800 | 0.5164 | -1.72 | Neutral | 0.152 | Benign | 0.070 | Benign | 2.81 | Benign | 0.18 | Tolerated | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.785A>C | N262T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262T has no ClinVar record and is not reported in gnomAD. Functional prediction tools cluster into three groups: benign predictions come from SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; the remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta’s stability analysis is uncertain. Overall, the balance of evidence leans toward pathogenicity, with no conflict with ClinVar status (which is absent). 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. | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -11.478 | Likely Pathogenic | 0.544 | Ambiguous | Likely Benign | 0.723 | Likely Pathogenic | 0.1055 | 0.5164 | 1.40 | Ambiguous | 0.3 | 1.44 | Ambiguous | 1.42 | Ambiguous | 0.74 | Ambiguous | -5.23 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.88 | Benign | 0.19 | Tolerated | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||
| c.230G>T | S77I 2D AIThe SynGAP1 missense variant S77I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -3.918 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.038 | Likely Benign | 0.0758 | 0.5165 | -1.41 | Neutral | 0.604 | Possibly Damaging | 0.029 | Benign | 4.07 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3400A>C | T1134P 2D AIThe SynGAP1 missense variant T1134P is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -2.993 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.164 | Likely Benign | 0.2001 | 0.5165 | -0.57 | Neutral | 0.013 | Benign | 0.022 | Benign | 5.41 | Benign | 0.07 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1272 | 0.5168 | -1.57 | Neutral | 0.975 | Probably Damaging | 0.850 | Possibly Damaging | 2.63 | Benign | 0.05 | Affected | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||
| c.1388A>C | D463A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463A missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely pathogenic, and Foldetta predicts a benign effect on protein stability. Overall, the majority of tools and the consensus high‑accuracy prediction lean toward pathogenicity, 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 | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -8.607 | Likely Pathogenic | 0.894 | Likely Pathogenic | Ambiguous | 0.425 | Likely Benign | 0.3591 | 0.5169 | -0.04 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.46 | Likely Benign | 0.43 | Likely Benign | -6.96 | Deleterious | 0.978 | Probably Damaging | 0.602 | Possibly Damaging | 3.33 | Benign | 0.29 | Tolerated | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.26A>C | H9P 2D  AIThe SynGAP1 missense variant H9P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.528099 | Binding | 0.394 | 0.916 | 0.750 | -2.838 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.224 | Likely Benign | 0.2644 | 0.5169 | -0.16 | Neutral | 0.107 | Benign | 0.006 | Benign | 4.19 | Benign | 0.00 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||
| c.3590A>C | E1197A 2D AIThe SynGAP1 missense variant E1197A is not 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, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Consequently, the evidence is balanced between benign and pathogenic predictions, with no high‑confidence support for either outcome. The variant is most likely benign based on the current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -4.852 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.442 | Likely Benign | 0.2811 | 0.5169 | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.45 | Benign | 0.09 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2541 | 0.5170 | -1.83 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 3.77 | 5 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||
| c.2350G>T | A784S 2D AIThe SynGAP1 missense variant A784S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | -2.233 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.2624 | 0.5171 | 0.41 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.72 | Benign | 0.67 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.538T>A | S180T 2D AIThe SynGAP1 missense variant S180T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -9.851 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 0.1238 | 0.5171 | -2.07 | Neutral | 0.057 | Benign | 0.020 | Benign | 3.86 | Benign | 0.02 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.2468G>A | S823N 2D AIThe SynGAP1 missense variant S823N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign votes). 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 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. | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.880 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | 0.1370 | 0.5172 | -1.76 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.94A>T | T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | -2.618 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.062 | Likely Benign | 0.3603 | 0.5174 | -0.39 | Neutral | 0.171 | Benign | 0.050 | Benign | 4.18 | Benign | 0.00 | Affected | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.95C>G | T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | -2.618 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.024 | Likely Benign | 0.3603 | 0.5174 | -0.39 | Neutral | 0.171 | Benign | 0.050 | Benign | 4.18 | Benign | 0.00 | Affected | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.1193C>A | P398Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P398Q has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -7.402 | In-Between | 0.792 | Likely Pathogenic | Ambiguous | 0.719 | Likely Pathogenic | 0.1522 | 0.5176 | 2.13 | Destabilizing | 0.1 | 2.01 | Destabilizing | 2.07 | Destabilizing | 1.01 | Destabilizing | -5.57 | Deleterious | 0.996 | Probably Damaging | 0.724 | Possibly Damaging | 5.48 | Benign | 0.00 | Affected | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||
| c.41C>A | P14H 2D AIThe SynGAP1 missense variant P14H is listed in gnomAD (ID 6‑33420305‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the majority of predictions—including the high‑accuracy tools—indicate that P14H 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | 6-33420305-C-A | -3.747 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.171 | Likely Benign | 0.1999 | 0.5176 | -0.27 | Neutral | 0.742 | Possibly Damaging | 0.091 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.1389C>A | D463E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.162 | Likely Benign | 0.1330 | 0.5177 | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.1389C>G | D463E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign, and Foldetta also indicates benign stability. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.162 | Likely Benign | 0.1330 | 0.5177 | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.20C>T | S7F 2D AIThe SynGAP1 missense variant S7F is not 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, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. AlphaMissense‑Optimized independently predicts 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 impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -4.346 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.171 | Likely Benign | 0.0622 | 0.5177 | -0.24 | Neutral | 0.296 | Benign | 0.032 | Benign | 4.06 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.763G>T | D255Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.180 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.832 | Likely Pathogenic | 0.0464 | 0.5178 | 1.25 | Ambiguous | 0.2 | 0.96 | Ambiguous | 1.11 | Ambiguous | 0.13 | Likely Benign | -7.77 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||
| 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 | 0.2098 | 0.5181 | -2.35 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||
| c.2384C>A | P795H 2D AIThe SynGAP1 missense variant P795H 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, while polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic outcome. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.972450 | Disordered | 0.410339 | Uncertain | 0.457 | 0.903 | 0.875 | -7.717 | In-Between | 0.121 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 0.1947 | 0.5184 | -0.61 | Neutral | 0.898 | Possibly Damaging | 0.477 | Possibly Damaging | 4.24 | Benign | 0.05 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||
| c.2857C>T | P953S 2D AIThe SynGAP1 missense variant P953S 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, 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 | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -5.430 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 0.3359 | 0.5184 | -0.35 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.96 | Benign | 0.37 | Tolerated | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.764A>G | D255G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255G 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 premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -12.652 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.885 | Likely Pathogenic | 0.3211 | 0.5185 | 1.72 | Ambiguous | 0.1 | 1.34 | Ambiguous | 1.53 | Ambiguous | 0.31 | Likely Benign | -6.13 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.86 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||
| c.1090C>G | P364A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P364A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Stability‑based methods (FoldX, Rosetta, premPS) give uncertain outcomes, and Foldetta is unavailable. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, does not provide a definitive result. Overall, the predictions are discordant; the majority of tools lean toward pathogenicity, but a substantial subset suggests benign. Based on the predictions, the variant is most likely pathogenic, and this does not contradict ClinVar status because there is no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -8.077 | Likely Pathogenic | 0.135 | Likely Benign | Likely Benign | 0.320 | Likely Benign | 0.3496 | 0.5186 | 0.79 | Ambiguous | 0.0 | 0.69 | Ambiguous | 0.74 | Ambiguous | 0.60 | Ambiguous | -6.10 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.56 | Pathogenic | 0.06 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.2267A>C | Q756P 2D AIThe SynGAP1 missense variant Q756P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.226 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.315 | Likely Benign | 0.2590 | 0.5186 | -0.93 | Neutral | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.54 | Pathogenic | 0.23 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3422C>A | P1141Q 2D AIThe SynGAP1 missense variant P1141Q is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, 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 evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.331 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.136 | Likely Benign | 0.1449 | 0.5186 | -2.72 | Deleterious | 0.074 | Benign | 0.047 | Benign | 0.97 | Pathogenic | 0.00 | Affected | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3436C>T | P1146S 2D AIThe SynGAP1 missense variant P1146S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33444471-C‑T). 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. 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 is consistent with the lack 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 | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | 6-33444471-C-T | 2 | 1.24e-6 | -3.045 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.470 | Likely Benign | 0.3408 | 0.5186 | -3.66 | Deleterious | 0.945 | Possibly Damaging | 0.760 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 4.32 | 4 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.757A>G | N253D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on benign effects include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, whereas Foldetta predicts a benign effect on protein stability. Overall, the majority of tools (8/15) favor a pathogenic outcome, with no conflict with ClinVar status because the variant is not yet catalogued. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -14.105 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.742 | Likely Pathogenic | 0.2248 | 0.5186 | 0.25 | Likely Benign | 0.0 | 0.37 | Likely Benign | 0.31 | Likely Benign | 0.09 | Likely Benign | -4.13 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.60 | Benign | 0.09 | Tolerated | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||
| c.66A>C | R22S 2D AIThe SynGAP1 missense variant R22S is 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, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, 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; a Foldetta stability prediction is 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 | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | -3.419 | Likely Benign | 0.602 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | 0.3252 | 0.5187 | 0.01 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||
| c.66A>T | R22S 2D AIThe SynGAP1 missense variant R22S is listed in gnomAD (ID 6‑33420330‑A‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its stability impact is unavailable. Overall, the majority of evidence points to a benign effect, and this is not in conflict with ClinVar, which has no classification for R22S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420330-A-T | -3.419 | Likely Benign | 0.602 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | 0.3252 | 0.5187 | 0.01 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||
| 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 | 0.2205 | 0.5188 | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2030 | 0.5188 | -1.52 | Neutral | 0.622 | Possibly Damaging | 0.165 | Benign | 2.61 | Benign | 0.37 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.1700A>C | E567A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E567A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Four tools (Foldetta, premPS, Rosetta, AlphaMissense‑Optimized) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by 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 | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -12.854 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | 0.3170 | 0.5189 | 0.43 | Likely Benign | 0.1 | 1.79 | Ambiguous | 1.11 | Ambiguous | 0.63 | Ambiguous | -5.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.17 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.2821C>G | P941A 2D AIThe SynGAP1 missense variant P941A is reported in gnomAD (variant ID 6-33443373-C-G) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, and AlphaMissense‑Optimized concurs with a benign prediction. Foldetta, a protein‑folding stability method, did not provide a result for this variant, so its status remains unavailable. Overall, the collective evidence strongly supports a benign classification, and this assessment is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-G | 2 | 1.24e-6 | -4.313 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.2844 | 0.5190 | 0.10 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.80 | Benign | 0.10 | Tolerated | 4.32 | 4 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.3961C>T | P1321S 2D AIThe SynGAP1 missense variant P1321S is listed in ClinVar (ID 1806027.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33451835‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.3610 | 0.5190 | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||
| c.401G>T | S134I 2D AIThe SynGAP1 missense variant S134I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -8.860 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.0683 | 0.5191 | -3.27 | Deleterious | 0.041 | Benign | 0.031 | Benign | 3.81 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.1178G>C | G393A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -4.507 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.381 | Likely Benign | 0.4143 | 0.5193 | 1.93 | Ambiguous | 0.5 | -0.68 | Ambiguous | 0.63 | Ambiguous | 0.22 | Likely Benign | -1.89 | Neutral | 0.176 | Benign | 0.039 | Benign | 1.33 | Pathogenic | 0.08 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.2891A>T | H964L 2D AIThe SynGAP1 missense variant H964L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) indicates likely benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.990547 | Disordered | 0.982486 | Binding | 0.364 | 0.886 | 0.750 | -7.568 | In-Between | 0.092 | Likely Benign | Likely Benign | 0.129 | Likely Benign | 0.1409 | 0.5195 | -1.20 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.02 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.3074A>C | Q1025P 2D AIThe SynGAP1 missense variant Q1025P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -2.151 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.153 | Likely Benign | 0.2211 | 0.5196 | -1.22 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.72 | Benign | 0.11 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.44C>G | A15G 2D AIThe SynGAP1 missense variant A15G is reported in gnomAD (ID 6‑33420308‑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, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports 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 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 | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | 6-33420308-C-G | 3 | 1.95e-6 | -3.261 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.2753 | 0.5196 | -0.04 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1375G>A | G459S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -10.979 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | 0.2340 | 0.5197 | 2.34 | Destabilizing | 0.1 | 0.77 | Ambiguous | 1.56 | Ambiguous | 0.60 | Ambiguous | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.09 | Benign | 0.05 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.3263G>A | S1088N 2D AIThe SynGAP1 missense variant S1088N has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM‑Consensus (derived from the four high‑accuracy tools) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a benign impact, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -5.227 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.1940 | 0.5197 | -1.25 | Neutral | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.622C>A | P208T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta; premPS and Rosetta are uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With the majority of tools, including the high‑accuracy ones, indicating pathogenicity, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -9.016 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.270 | Likely Benign | 0.1857 | 0.5197 | 3.20 | Destabilizing | 0.5 | 1.27 | Ambiguous | 2.24 | Destabilizing | 0.94 | Ambiguous | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.76 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.2924C>T | T975I 2D AIThe SynGAP1 missense variant T975I is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33443476‑C‑T). Prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | 6-33443476-C-T | 6 | 3.72e-6 | -3.912 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.1107 | 0.5198 | -1.66 | Neutral | 0.411 | Benign | 0.239 | Benign | 4.11 | Benign | 0.66 | Tolerated | 4.32 | 2 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||
| c.1558T>A | S520T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520T is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS and PROVEAN, while pathogenic predictions are made by SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four high‑accuracy methods were examined: AlphaMissense‑Optimized returned an uncertain result; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, was also uncertain. With three of the four high‑accuracy tools indicating pathogenicity and only two tools suggesting benign, the overall evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.432 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.565 | Likely Pathogenic | 0.1296 | 0.5199 | 0.52 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.52 | Ambiguous | 0.34 | Likely Benign | -2.41 | Neutral | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.28 | Pathogenic | 0.02 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1858T>A | S620T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized, and Rosetta. Those that predict pathogenicity are SGM‑Consensus, REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of tools lean toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -9.171 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 0.551 | Likely Pathogenic | 0.1288 | 0.5199 | 0.52 | Ambiguous | 0.1 | -0.40 | Likely Benign | 0.06 | Likely Benign | 0.30 | Likely Benign | -1.99 | Neutral | 0.896 | Possibly Damaging | 0.933 | Probably Damaging | -1.25 | Pathogenic | 0.14 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.297A>C | E99D 2D AIThe SynGAP1 missense variant E99D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E99D 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 | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.323 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.2360 | 0.5200 | -0.78 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.297A>T | E99D 2D AIThe SynGAP1 missense variant E99D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E99D 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 | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.323 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.2360 | 0.5200 | -0.78 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.1337A>G | E446G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. The majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -11.457 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.510 | Likely Pathogenic | 0.2665 | 0.5202 | 2.62 | Destabilizing | 0.7 | 1.63 | Ambiguous | 2.13 | Destabilizing | 0.83 | Ambiguous | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| 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 | 0.0828 | 0.5202 | -2.88 | Deleterious | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 2.59 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2974G>C | V992L 2D AIThe SynGAP1 missense variant V992L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -2.333 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1211 | 0.5202 | -0.50 | Neutral | 0.086 | Benign | 0.038 | Benign | 4.24 | Benign | 0.16 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3124C>A | Q1042K 2D AIThe SynGAP1 missense variant Q1042K 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, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective predictions strongly suggest that 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 | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.331 | Likely Benign | 0.498 | Ambiguous | Likely Benign | 0.304 | Likely Benign | 0.2338 | 0.5202 | -1.52 | Neutral | 0.224 | Benign | 0.091 | Benign | 5.44 | Benign | 0.13 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.896G>T | R299L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of consensus predictions favor a pathogenic effect, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for R299L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -5.171 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.356 | Likely Benign | 0.2027 | 0.5202 | 1.37 | Ambiguous | 0.6 | 0.77 | Ambiguous | 1.07 | Ambiguous | 0.59 | Ambiguous | -4.03 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.2857C>G | P953A 2D AIThe SynGAP1 missense variant P953A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates pathogenicity. High‑accuracy assessments reinforce this view: 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, so they do not alter the overall assessment. Consequently, the variant is most likely benign based on the collective 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 Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -4.879 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.3476 | 0.5203 | -0.98 | Neutral | 0.124 | Benign | 0.061 | Benign | 2.81 | Benign | 0.41 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.140G>T | R47L 2D AIThe SynGAP1 missense variant R47L is 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) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R47L. 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 | 0.318242 | Structured | 0.436559 | Uncertain | 0.520 | 0.719 | 0.125 | -5.758 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.130 | Likely Benign | 0.1904 | 0.5206 | -1.76 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.2557G>A | G853S 2D AIThe SynGAP1 missense variant G853S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G853S is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.496246 | Uncertain | 0.284 | 0.815 | 0.625 | -3.878 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.155 | Likely Benign | 0.2783 | 0.5206 | 0.14 | Neutral | 0.003 | Benign | 0.008 | Benign | 4.31 | Benign | 0.02 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1367 | 0.5206 | -2.78 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3292A>G | S1098G 2D AIThe SynGAP1 missense variant S1098G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the collective predictions strongly support a benign impact, and this conclusion is consistent with the lack of a ClinVar pathogenic classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -3.494 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.2634 | 0.5206 | -0.39 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.72 | Benign | 0.57 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.2663C>G | A888G 2D AIThe SynGAP1 missense variant A888G is reported in gnomAD (ID 6‑33443215‑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, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, representing a single dissenting opinion. 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 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 | 0.784345 | Disordered | 0.575860 | Binding | 0.352 | 0.928 | 0.625 | 6-33443215-C-G | 5 | 3.10e-6 | -2.523 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 0.2312 | 0.5207 | -0.32 | Neutral | 0.033 | Benign | 0.036 | Benign | 2.69 | Benign | 0.00 | Affected | 4.32 | 4 | 0 | 1 | -2.2 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||
| c.3827A>T | D1276V 2D AIThe SynGAP1 D1276V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, 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 | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.725 | Likely Benign | 0.851 | Likely Pathogenic | Ambiguous | 0.331 | Likely Benign | 0.0614 | 0.5207 | -6.66 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.19 | Pathogenic | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.602A>T | D201V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. With the majority of tools indicating pathogenicity and no ClinVar record to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.283 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | 0.0572 | 0.5207 | 0.87 | Ambiguous | 0.1 | 2.18 | Destabilizing | 1.53 | Ambiguous | 0.31 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.02 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.1967A>G | E656G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E656G missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Only premPS and FATHMM predict a benign outcome, while FoldX and Foldetta are inconclusive. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E656G, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -14.112 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.534 | Likely Pathogenic | 0.3216 | 0.5208 | 0.96 | Ambiguous | 0.1 | 2.02 | Destabilizing | 1.49 | Ambiguous | 0.22 | Likely Benign | -6.28 | Deleterious | 1.000 | Probably Damaging | 0.941 | Probably Damaging | 3.44 | Benign | 0.05 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.2040G>C | E680D 2D AIThe SynGAP1 missense variant E680D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -5.019 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.2199 | 0.5208 | 0.21 | Likely Benign | 0.8 | 0.27 | Likely Benign | 0.24 | Likely Benign | -0.10 | Likely Benign | -0.64 | Neutral | 0.906 | Possibly Damaging | 0.295 | Benign | 3.66 | Benign | 0.32 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.2040G>T | E680D 2D AIThe SynGAP1 missense variant E680D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or likely benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, representing the sole discordant prediction. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding‑stability result is missing or inconclusive. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -5.019 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.2199 | 0.5208 | 0.21 | Likely Benign | 0.8 | 0.27 | Likely Benign | 0.24 | Likely Benign | -0.10 | Likely Benign | -0.64 | Neutral | 0.906 | Possibly Damaging | 0.295 | Benign | 3.66 | Benign | 0.32 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.2404G>A | G802S 2D AIThe SynGAP1 missense variant G802S is catalogued in gnomAD (allele ID 6‑33442956‑G‑A) but has no entry in ClinVar. Functional prediction tools that assess evolutionary conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all uniformly predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely 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 variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | 6-33442956-G-A | 1 | 6.20e-7 | -2.663 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.2682 | 0.5208 | 0.32 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.83 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0 | 1 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2380C>G | P794A 2D AIThe SynGAP1 missense variant P794A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). 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 results are unavailable, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -3.766 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.038 | Likely Benign | 0.3692 | 0.5209 | -0.63 | Neutral | 0.124 | Benign | 0.089 | Benign | 4.27 | Benign | 0.09 | Tolerated | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.770G>T | S257I 2D AIThe SynGAP1 missense variant S257I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting a benign outcome. FoldX and Rosetta results are uncertain and therefore not considered. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -12.126 | Likely Pathogenic | 0.595 | Likely Pathogenic | Likely Benign | 0.739 | Likely Pathogenic | 0.0681 | 0.5209 | 0.78 | Ambiguous | 1.0 | -1.17 | Ambiguous | -0.20 | Likely Benign | 0.30 | Likely Benign | -2.97 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.81 | Benign | 0.07 | Tolerated | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| c.3476C>T | S1159F 2D AIThe SynGAP1 missense variant S1159F 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 (majority vote) which classifies the variant as 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 AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains benign; Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -5.627 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | 0.0527 | 0.5211 | -1.11 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.20 | Tolerated | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.763G>C | D255H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of the available predictions points to a pathogenic effect for D255H, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -14.645 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.808 | Likely Pathogenic | 0.1447 | 0.5211 | 1.72 | Ambiguous | 0.2 | 1.17 | Ambiguous | 1.45 | Ambiguous | 0.44 | Likely Benign | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||
| c.2929G>C | A977P 2D AIThe SynGAP1 missense variant A977P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A977P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.665 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.094 | Likely Benign | 0.2405 | 0.5212 | -1.12 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 3.94 | Benign | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.313T>A | S105T 2D AIThe SynGAP1 missense variant S105T 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 high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant 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, 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 | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | -4.166 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.1583 | 0.5212 | -0.54 | Neutral | 0.012 | Benign | 0.007 | Benign | 4.06 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.326G>C | S109T 2D AIThe SynGAP1 missense variant S109T is catalogued in gnomAD (6‑33432191‑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‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus, derived from the majority of the high‑accuracy predictors, is benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S109T is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | 6-33432191-G-C | 2 | 1.24e-6 | -4.065 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.090 | Likely Benign | 0.1519 | 0.5212 | -1.19 | Neutral | 0.231 | Benign | 0.050 | Benign | 3.59 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1082A>T | Q361L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q361L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8 benign vs 5 pathogenic) favor a benign effect, and this consensus does not contradict the absence of a ClinVar classification. 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. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -10.678 | Likely Pathogenic | 0.238 | Likely Benign | Likely Benign | 0.406 | Likely Benign | 0.0720 | 0.5213 | 0.12 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.29 | Likely Benign | 0.21 | Likely Benign | -3.95 | Deleterious | 0.987 | Probably Damaging | 0.953 | Probably Damaging | 1.71 | Pathogenic | 0.06 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||
| c.3826G>A | D1276N 2D AIThe SynGAP1 missense variant D1276N is not 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, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy consensus also leans pathogenic. Therefore, 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. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 3.371 | Likely Benign | 0.473 | Ambiguous | Likely Benign | 0.242 | Likely Benign | 0.0883 | 0.5213 | -3.68 | Deleterious | 0.899 | Possibly Damaging | 0.581 | Possibly Damaging | 1.22 | Pathogenic | 0.00 | Affected | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1898 | 0.5214 | -4.03 | Deleterious | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||
| c.3298G>C | G1100R 2D AIThe SynGAP1 missense variant G1100R is not 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 assessments show AlphaMissense‑Optimized as benign; 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 lean toward pathogenicity, and this does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.923 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.176 | Likely Benign | 0.0986 | 0.5217 | -2.05 | Neutral | 0.992 | Probably Damaging | 0.906 | Possibly Damaging | 1.92 | Pathogenic | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3301C>G | P1101A 2D AIThe SynGAP1 missense variant P1101A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -3.825 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.3154 | 0.5218 | -1.34 | Neutral | 0.010 | Benign | 0.010 | Benign | 4.26 | Benign | 0.08 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.597C>A | N199K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign. Only ESM1b and AlphaMissense‑Default predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the preponderance of evidence supports a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | Uncertain | 1 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 0.024 | Likely Benign | 0.1399 | 0.5218 | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.597C>G | N199K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b 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. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence (10 benign vs. 2 pathogenic) supports a benign classification. This consensus does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 0.024 | Likely Benign | 0.1399 | 0.5218 | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||
| c.273G>C | E91D 2D AIThe SynGAP1 missense variant E91D is reported in gnomAD (variant ID 6‑33425881‑G‑C) 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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, 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 | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | 6-33425881-G-C | 1 | 6.20e-7 | -3.160 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.2000 | 0.5219 | -0.84 | Neutral | 0.880 | Possibly Damaging | 0.636 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.273G>T | E91D 2D AIThe SynGAP1 missense variant E91D 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 result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.533667 | Binding | 0.303 | 0.875 | 0.500 | -3.160 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.2000 | 0.5219 | -0.84 | Neutral | 0.880 | Possibly Damaging | 0.636 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||
| c.79C>G | P27A 2D AIThe SynGAP1 missense variant P27A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27A, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.409 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.4041 | 0.5219 | -1.98 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.2777C>T | S926F 2D AIThe SynGAP1 missense variant S926F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S926F 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.157 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.458 | Likely Benign | 0.0585 | 0.5220 | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2096 | 0.5220 | -1.72 | Neutral | 0.011 | Benign | 0.005 | Benign | 2.58 | Benign | 0.05 | Affected | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.632G>T | S211I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S211I missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the preponderance of evidence indicates 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 | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -17.090 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | 0.0909 | 0.5220 | 1.06 | Ambiguous | 1.1 | 1.05 | Ambiguous | 1.06 | Ambiguous | 0.12 | Likely Benign | -4.94 | Deleterious | 0.995 | Probably Damaging | 0.767 | Possibly Damaging | 3.90 | Benign | 0.01 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| c.680G>C | G227A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that remain uncertain are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -7.344 | In-Between | 0.920 | Likely Pathogenic | Ambiguous | 0.682 | Likely Pathogenic | 0.3987 | 0.5221 | 2.45 | Destabilizing | 0.4 | 5.14 | Destabilizing | 3.80 | Destabilizing | 0.78 | Ambiguous | -5.08 | Deleterious | 0.097 | Benign | 0.023 | Benign | 5.71 | Benign | 0.04 | Affected | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||
| c.930G>C | E310D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E310D is reported in ClinVar (ID 975473.0) as Pathogenic and is not found in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, leaving no tool in the benign category. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports Pathogenic. The single uncertain result from FoldX is treated as unavailable. Overall, the variant is most likely pathogenic, and this assessment is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Likely Pathogenic | 1 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.666 | Likely Pathogenic | 0.1981 | 0.5222 | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | ||||||||||||
| c.930G>T | E310D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL (Pathogenic), Rosetta (Pathogenic), Foldetta (Pathogenic), premPS (Pathogenic), PROVEAN (Pathogenic), polyPhen‑2 HumDiv (Pathogenic), polyPhen‑2 HumVar (Pathogenic), SIFT (Pathogenic), ESM1b (Pathogenic), FATHMM (Pathogenic), AlphaMissense‑Default (Pathogenic), and AlphaMissense‑Optimized (Pathogenic). No tool predicts a benign outcome; the only inconclusive result is FoldX (Uncertain). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for E310D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.666 | Likely Pathogenic | 0.1981 | 0.5222 | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | ||||||||||||||
| c.2561G>T | R854L 2D AIThe SynGAP1 missense variant R854L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R854L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.488780 | Uncertain | 0.277 | 0.815 | 0.750 | -2.573 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.131 | Likely Benign | 0.1875 | 0.5223 | -1.78 | Neutral | 0.960 | Probably Damaging | 0.765 | Possibly Damaging | 4.11 | Benign | 0.03 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.2576G>A | S859N 2D AIThe SynGAP1 missense variant S859N 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 does not contradict the ClinVar status, which contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -8.184 | Likely Pathogenic | 0.225 | Likely Benign | Likely Benign | 0.142 | Likely Benign | 0.1221 | 0.5226 | -0.62 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 3.99 | Benign | 0.29 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.70G>C | V24L 2D AIThe SynGAP1 missense variant V24L is not 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.1102 | 0.5226 | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.70G>T | V24L 2D AIThe SynGAP1 missense variant V24L is not 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.1102 | 0.5226 | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1813C>A | P605T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605T 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, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy methods specifically show pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -11.533 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.801 | Likely Pathogenic | 0.1626 | 0.5228 | 2.87 | Destabilizing | 0.4 | 2.14 | Destabilizing | 2.51 | Destabilizing | 0.72 | Ambiguous | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.2389C>T | P797S 2D AIThe SynGAP1 missense variant P797S 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 tolerated or benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for P797S, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.926919 | Disordered | 0.449970 | Uncertain | 0.561 | 0.902 | 0.875 | -6.232 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.029 | Likely Benign | 0.3634 | 0.5228 | -0.14 | Neutral | 0.901 | Possibly Damaging | 0.637 | Possibly Damaging | 4.25 | Benign | 0.38 | Tolerated | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.589G>C | E197Q 2D AIThe SynGAP1 E197Q variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -6.347 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | 0.0867 | 0.5228 | -1.75 | Neutral | 0.396 | Benign | 0.067 | Benign | 4.05 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.663G>C | E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta remains uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.237 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 0.1755 | 0.5228 | 1.59 | Ambiguous | 0.1 | 1.07 | Ambiguous | 1.33 | Ambiguous | 0.84 | Ambiguous | -2.43 | Neutral | 0.421 | Benign | 0.107 | Benign | 5.80 | Benign | 0.02 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.663G>T | E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.237 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 0.1755 | 0.5228 | 1.59 | Ambiguous | 0.1 | 1.07 | Ambiguous | 1.33 | Ambiguous | 0.84 | Ambiguous | -2.43 | Neutral | 0.421 | Benign | 0.107 | Benign | 5.80 | Benign | 0.02 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.137C>A | P46H 2D AIThe SynGAP1 missense variant P46H is evaluated by multiple in silico tools. Consensus from SGM‑Consensus indicates a likely benign effect, and the variant is not reported in ClinVar or gnomAD. Functional predictors that agree on a benign outcome include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Predictors that flag a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports likely benign, while Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for P46H, and this conclusion is not contradicted by any ClinVar annotation. The variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | -4.022 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.097 | Likely Benign | 0.2360 | 0.5229 | -0.43 | Neutral | 0.992 | Probably Damaging | 0.977 | Probably Damaging | 4.10 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.1190G>T | C397F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397F is reported in gnomAD (6-33438095-G-T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the protein‑folding stability method Foldetta. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, while Foldetta indicates a pathogenic effect. Because the majority of tools (nine benign vs. four pathogenic) lean toward a benign outcome and the high‑accuracy consensus is split, the variant is most likely benign. 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 Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | 6-33438095-G-T | 1 | 6.20e-7 | -6.571 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.493 | Likely Benign | 0.1426 | 0.5231 | 1.31 | Ambiguous | 1.7 | 3.61 | Destabilizing | 2.46 | Destabilizing | 0.12 | Likely Benign | -1.95 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.65 | Benign | 0.07 | Tolerated | 3.41 | 15 | -2 | -4 | 0.3 | 44.04 | ||||||||||||||||||||
| 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 | 0.2971 | 0.5231 | -5.10 | Deleterious | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.698G>T | C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.564 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.901 | Likely Pathogenic | 0.1524 | 0.5231 | 9.36 | Destabilizing | 3.0 | -0.19 | Likely Benign | 4.59 | Destabilizing | 0.37 | Likely Benign | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.73 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| c.1177G>A | G393S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, polyPhen‑2 HumDiv, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other tools provide decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect, and this consensus does not conflict with the absence of ClinVar annotation. Therefore, G393S is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -5.207 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.466 | Likely Benign | 0.3011 | 0.5232 | 2.43 | Destabilizing | 0.7 | -0.78 | Ambiguous | 0.83 | Ambiguous | 0.24 | Likely Benign | -1.76 | Neutral | 0.889 | Possibly Damaging | 0.444 | Benign | 1.33 | Pathogenic | 0.07 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.1334A>T | E445V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of evidence points toward a pathogenic effect. 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 | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -14.830 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.572 | Likely Pathogenic | 0.0414 | 0.5233 | 0.34 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.17 | Likely Benign | 0.32 | Likely Benign | -6.68 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.3395C>A | S1132Y 2D AIThe SynGAP1 missense variant S1132Y is listed in ClinVar as a benign alteration (ClinVar ID 845357.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | Likely Benign | 1 | -5.894 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.401 | Likely Benign | 0.0889 | 0.5233 | -1.76 | Neutral | 0.500 | Possibly Damaging | 0.208 | Benign | 5.40 | Benign | 0.09 | Tolerated | 4.32 | 4 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||
| c.2983C>T | P995S 2D AIThe SynGAP1 missense variant P995S is listed in ClinVar (ID 436929.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The only tool that predicts a pathogenic outcome is SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta) stability result is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, point to a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | Uncertain | 1 | -4.457 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.3204 | 0.5236 | -1.03 | Neutral | 0.011 | Benign | 0.015 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.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 | 0.0957 | 0.5236 | -3.13 | Deleterious | 0.004 | Benign | 0.004 | Benign | 2.48 | Pathogenic | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.611C>G | S204C 2D 3DClick to see structure in 3D Viewer AISynGAP1 S204C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. FoldX and Rosetta individually report uncertain stability changes. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | Uncertain | 1 | -6.613 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.0665 | 0.5237 | 0.65 | Ambiguous | 0.4 | -1.13 | Ambiguous | -0.24 | Likely Benign | 0.10 | Likely Benign | -0.64 | Neutral | 0.978 | Probably Damaging | 0.753 | Possibly Damaging | 4.13 | Benign | 0.05 | Affected | 3.44 | 10 | 0 | -1 | 3.3 | 16.06 | 223.6 | -13.8 | 0.6 | 0.3 | 0.0 | 0.2 | X | Uncertain | The hydroxyl-containing Ser204, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by the thiol-containing cysteine. In the WT simulations, Ser204 simultaneously forms hydrogen bonds with the backbone carbonyl of Asp201 and the hydroxyl group of Thr224, helping to stabilize the two anti-parallel β strands (res. Ile205-Lys207 and Cys219-Thr223) at the end of the β sheet. Since the thiol group of cysteine forms weaker hydrogen bonds than the hydroxyl group of serine, Cys204 does not maintain the hydrogen bond network as stably as Ser204 in the variant simulations. However, because the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
| c.3496G>T | A1166S 2D AIThe SynGAP1 missense variant A1166S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification. Consequently, the variant is most likely benign according to the majority of predictive evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -2.587 | Likely Benign | 0.396 | Ambiguous | Likely Benign | 0.308 | Likely Benign | 0.2568 | 0.5239 | -0.59 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 5.41 | Benign | 0.35 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| 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 | 0.603 | Likely Pathogenic | 0.1397 | 0.5240 | 2.56 | Destabilizing | 0.1 | 1.11 | Ambiguous | 1.84 | Ambiguous | 1.34 | Destabilizing | -3.98 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.768C>A | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, 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) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools favor a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, 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. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.569 | Likely Pathogenic | 0.1702 | 0.5240 | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.768C>G | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, 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) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools support a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.569 | Likely Pathogenic | 0.1702 | 0.5240 | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.1067G>T | R356L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356L is not reported in ClinVar and is present in gnomAD (ID 6‑33437972‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, and Foldetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for R356L, and this conclusion does not contradict 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 | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | 6-33437972-G-T | -13.957 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.412 | Likely Benign | 0.2110 | 0.5242 | -0.04 | Likely Benign | 0.1 | -0.57 | Ambiguous | -0.31 | Likely Benign | 0.68 | Ambiguous | -6.20 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 22 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||
| c.1124G>C | G375A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect; this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -5.986 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.419 | Likely Benign | 0.3991 | 0.5242 | 2.52 | Destabilizing | 1.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | -0.09 | Likely Benign | -0.61 | Neutral | 0.020 | Benign | 0.008 | Benign | 1.33 | Pathogenic | 0.27 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1198G>C | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is listed in ClinVar as Benign (ClinVar ID 1166313.0) and is present in gnomAD (variant ID 6‑33438103‑G‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX, which is treated as unavailable. High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Benign | 1 | 6-33438103-G-C | 22 | 1.36e-5 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.325 | Likely Benign | 0.1006 | 0.5242 | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||
| c.1198G>T | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.325 | Likely Benign | 0.1006 | 0.5242 | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||
| c.3562G>C | D1188H 2D AIThe SynGAP1 D1188H 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, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; 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 evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this prediction 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 | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -6.827 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | 0.0892 | 0.5242 | -3.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.41 | Benign | 0.00 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.553T>C | S185P 2D AIThe SynGAP1 missense variant S185P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as 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 the S185P 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 | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -15.129 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | 0.2156 | 0.5242 | -4.02 | Deleterious | 0.940 | Possibly Damaging | 0.462 | Possibly Damaging | 3.56 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.29G>C | R10P 2D AIThe SynGAP1 missense variant R10P is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33420293‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) is benign; Foldetta results are unavailable. Overall, the collective evidence points to a benign effect for R10P, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.513657 | Binding | 0.330 | 0.915 | 0.625 | Uncertain | 2 | 6-33420293-G-C | 2 | 1.30e-6 | -3.772 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.220 | Likely Benign | 0.2261 | 0.5245 | -0.05 | Neutral | 0.233 | Benign | 0.026 | Benign | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||
| c.1109G>C | G370A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from FoldX, Foldetta, and FATHMM, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicating a likely benign outcome, and Foldetta suggesting a pathogenic impact via combined FoldX‑MD and Rosetta stability analysis. Overall, the majority of evidence points to a benign effect, with only a minority of tools predicting pathogenicity. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -3.334 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.304 | Likely Benign | 0.3883 | 0.5247 | 2.44 | Destabilizing | 1.3 | 1.62 | Ambiguous | 2.03 | Destabilizing | -0.14 | Likely Benign | 0.54 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.79 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1115G>C | G372A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a benign impact for G372A, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -5.163 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.465 | Likely Benign | 0.3956 | 0.5247 | 1.52 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.55 | Ambiguous | -0.12 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.03 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.3827A>G | D1276G 2D AIThe SynGAP1 missense variant D1276G is not 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 include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from 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 and the SGM‑Consensus support a pathogenic interpretation, and there is no ClinVar record to contradict this assessment. 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 | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 0.509 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.293 | Likely Benign | 0.3429 | 0.5247 | -4.93 | Deleterious | 0.899 | Possibly Damaging | 0.655 | Possibly Damaging | 1.21 | Pathogenic | 0.00 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.3455A>G | E1152G 2D AIThe SynGAP1 missense variant E1152G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence points to a pathogenic effect for E1152G. This conclusion is not contradicted by 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 | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -2.663 | Likely Benign | 0.918 | Likely Pathogenic | Ambiguous | 0.373 | Likely Benign | 0.3242 | 0.5249 | -3.85 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.36 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.386C>T | S129L 2D AIThe SynGAP1 missense variant S129L is catalogued in gnomAD (ID 6‑33432251‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the preponderance of evidence indicates that S129L is most likely benign, 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. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | 6-33432251-C-T | 1 | 6.20e-7 | -4.487 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.256 | Likely Benign | 0.0885 | 0.5249 | -0.18 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.14 | Benign | 0.05 | Affected | 3.74 | 4 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||
| c.455G>T | R152L 2D AIThe SynGAP1 missense variant R152L 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 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 indicates that R152L 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 | 0.618285 | Disordered | 0.500158 | Binding | 0.319 | 0.842 | 0.625 | -11.501 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.331 | Likely Benign | 0.2032 | 0.5249 | -3.85 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.776G>C | R259P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this view: AlphaMissense‑Optimized scores the variant 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 predicts a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -14.876 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.902 | Likely Pathogenic | 0.2051 | 0.5249 | 6.34 | Destabilizing | 1.6 | 3.78 | Destabilizing | 5.06 | Destabilizing | 1.16 | Destabilizing | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.84 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.3137C>A | P1046H 2D AIThe SynGAP1 missense variant P1046H is not 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 (which is “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 also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for P1046H. 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 | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -5.715 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.035 | Likely Benign | 0.1585 | 0.5250 | -1.64 | Neutral | 0.832 | Possibly Damaging | 0.670 | Possibly Damaging | 2.33 | Pathogenic | 0.07 | Tolerated | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.2519G>T | S840I 2D AIThe SynGAP1 missense variant S840I is 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus indicates likely pathogenic. Foldetta results are not available, so they do not influence the overall assessment. Based on the consensus of the majority of prediction tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.611356 | Binding | 0.259 | 0.865 | 0.250 | -12.509 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.357 | Likely Benign | 0.0788 | 0.5251 | -4.31 | Deleterious | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2230 | 0.5251 | -0.87 | Neutral | 0.057 | Benign | 0.047 | Benign | 2.60 | Benign | 0.01 | Affected | 4.32 | 4 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.77G>C | G26A 2D AIThe SynGAP1 missense variant G26A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G26A, 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 | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -3.308 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.062 | Likely Benign | 0.4093 | 0.5251 | -1.25 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 4.02 | Benign | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3383G>C | G1128A 2D AIThe SynGAP1 missense variant G1128A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.015 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.209 | Likely Benign | 0.3588 | 0.5252 | -0.26 | Neutral | 0.009 | Benign | 0.008 | Benign | 4.47 | Benign | 0.46 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.731A>G | E244G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational evidence points to the variant being most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.452 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 0.2266 | 0.5252 | 1.28 | Ambiguous | 0.0 | 0.74 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | -5.67 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.73 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1756G>A | D586N 2D AIThe SynGAP1 D586N missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools that agree on benign impact include FoldX, Rosetta, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, more tools predict pathogenicity than benign, and the high‑accuracy consensus leans toward pathogenic. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -9.497 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.523 | Likely Pathogenic | 0.1124 | 0.5253 | 0.09 | Likely Benign | 0.8 | 0.24 | Likely Benign | 0.17 | Likely Benign | 0.19 | Likely Benign | -2.52 | Deleterious | 0.992 | Probably Damaging | 0.995 | Probably Damaging | -1.25 | Pathogenic | 0.23 | Tolerated | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.964G>T | A322S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. No prediction or stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -1.424 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.2696 | 0.5253 | 0.41 | Likely Benign | 0.2 | 0.38 | Likely Benign | 0.40 | Likely Benign | -0.44 | Likely Benign | 1.09 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 0.67 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1187G>C | G396A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.655 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.274 | Likely Benign | 0.3846 | 0.5255 | 1.74 | Ambiguous | 0.7 | 1.90 | Ambiguous | 1.82 | Ambiguous | 0.41 | Likely Benign | -1.28 | Neutral | 0.062 | Benign | 0.024 | Benign | 3.93 | Benign | 0.84 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1985A>T | Q662L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q662L is not 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, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Overall, the majority of evidence supports a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.046336 | Structured | 0.103446 | Uncertain | 0.932 | 0.323 | 0.000 | -10.291 | Likely Pathogenic | 0.300 | Likely Benign | Likely Benign | 0.186 | Likely Benign | 0.1070 | 0.5255 | 0.04 | Likely Benign | 0.0 | 0.12 | Likely Benign | 0.08 | Likely Benign | 0.17 | Likely Benign | -4.09 | Deleterious | 0.699 | Possibly Damaging | 0.057 | Benign | 3.42 | Benign | 0.10 | Tolerated | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||
| c.110C>A | S37Y 2D AIThe SynGAP1 missense variant S37Y is listed in gnomAD (ID 6‑33423519‑C‑A) 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 is missing. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | 6-33423519-C-A | 1 | 6.20e-7 | -4.447 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.132 | Likely Benign | 0.1247 | 0.5256 | -1.61 | Neutral | 0.880 | Possibly Damaging | 0.888 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.2395C>A | P799T 2D AIThe SynGAP1 missense variant P799T 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. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P799T, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.470 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.1522 | 0.5257 | -0.82 | Neutral | 0.951 | Possibly Damaging | 0.738 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3760G>C | E1254Q 2D AIThe SynGAP1 missense variant E1254Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—favors pathogenic (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -9.041 | Likely Pathogenic | 0.511 | Ambiguous | Likely Benign | 0.207 | Likely Benign | 0.0768 | 0.5258 | -2.18 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.35 | Pathogenic | 0.03 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3814G>C | E1272Q 2D AIThe SynGAP1 E1272Q missense variant is catalogued in gnomAD (variant ID 6‑33447862‑G‑C) but has no ClinVar entry. Prediction tools cluster into two groups: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote aggregator of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance 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, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447862-G-C | 1 | 6.45e-7 | -3.000 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.207 | Likely Benign | 0.0746 | 0.5258 | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.694G>C | A232P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P is 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, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -12.697 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.748 | Likely Pathogenic | 0.2163 | 0.5259 | 0.05 | Likely Benign | 0.8 | 1.25 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | -2.75 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 5.78 | Benign | 0.06 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.3452C>G | S1151C 2D AIThe SynGAP1 missense variant S1151C is reported in gnomAD (ID 6‑33444487‑C‑G) but has no ClinVar entry. 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 impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | 6-33444487-C-G | 1 | 6.20e-7 | -6.778 | Likely Benign | 0.225 | Likely Benign | Likely Benign | 0.181 | Likely Benign | 0.1056 | 0.5260 | -0.86 | Neutral | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.67 | Benign | 0.07 | Tolerated | 3.77 | 5 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.2138C>T | P713L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P713L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -11.323 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.1993 | 0.5261 | 0.18 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.08 | Likely Benign | 0.55 | Ambiguous | -8.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.29G>T | R10L 2D AIThe SynGAP1 missense variant R10L is not 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 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 | 0.534167 | Disordered | 0.513657 | Binding | 0.330 | 0.915 | 0.625 | -3.269 | Likely Benign | 0.244 | Likely Benign | Likely Benign | 0.143 | Likely Benign | 0.2255 | 0.5261 | 0.09 | Neutral | 0.058 | Benign | 0.009 | Benign | 4.21 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0767 | 0.5262 | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.06 | Tolerated | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||
| c.3098C>A | S1033Y 2D AIThe SynGAP1 missense variant S1033Y is reported in gnomAD (ID 6‑33443650‑C‑A) but has no ClinVar entry. 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 is benign and the SGM‑Consensus is 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 | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | 6-33443650-C-A | 1 | 6.19e-7 | -4.857 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.034 | Likely Benign | 0.0708 | 0.5262 | -1.01 | Neutral | 0.021 | Benign | 0.008 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.1547C>T | A516V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A516V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect fall into two groups: benign predictions come from FoldX, Rosetta, and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools, including the high‑accuracy predictors, lean toward 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 | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -11.545 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.639 | Likely Pathogenic | 0.1336 | 0.5263 | 0.42 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.29 | Likely Benign | 0.62 | Ambiguous | -3.61 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.32 | Pathogenic | 0.09 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1802C>T | A601V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601V is listed in ClinVar (ID 968190.0) with an uncertain clinical significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Uncertain | 1 | -10.447 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.535 | Likely Pathogenic | 0.1338 | 0.5263 | 1.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 1.00 | Ambiguous | 0.81 | Ambiguous | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.74 | Benign | 0.03 | Affected | 3.37 | 35 | 0 | 0 | 2.4 | 28.05 | 228.5 | -45.5 | 0.0 | 0.0 | 0.4 | 0.5 | X | Potentially Benign | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||||
| c.95C>A | T32N 2D AIThe SynGAP1 missense variant T32N is catalogued in gnomAD (ID 6‑33423504‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: 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 reported result for this variant, so its status is unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | 6-33423504-C-A | 2 | 1.24e-6 | -3.466 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.1681 | 0.5264 | -1.01 | Neutral | 0.604 | Possibly Damaging | 0.140 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||
| c.3589G>C | E1197Q 2D AIThe SynGAP1 missense variant E1197Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and no Foldetta stability data are available. Overall, the balance of evidence favors a benign interpretation, 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 | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -2.771 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.304 | Likely Benign | 0.0690 | 0.5265 | -0.60 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.44 | Benign | 0.29 | Tolerated | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.1838A>G | E613G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E613G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. No prediction or stability assessment is missing or inconclusive beyond the uncertain labels. Overall, the preponderance of evidence points to a pathogenic effect for E613G, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -12.417 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.641 | Likely Pathogenic | 0.3422 | 0.5266 | 1.49 | Ambiguous | 0.3 | 1.34 | Ambiguous | 1.42 | Ambiguous | 0.08 | Likely Benign | -6.56 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.2635G>T | A879S 2D AIThe SynGAP1 missense variant A879S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -3.406 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.2469 | 0.5266 | -0.26 | Neutral | 0.580 | Possibly Damaging | 0.324 | Benign | 2.68 | Benign | 0.44 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.2645G>C | G882A 2D AIThe SynGAP1 missense variant G882A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, whereas only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -3.876 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.048 | Likely Benign | 0.3345 | 0.5268 | -1.05 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.14 | Pathogenic | 0.79 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3279G>C | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1600 | 0.5269 | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3279G>T | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1600 | 0.5269 | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.704C>A | S235Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S235Y, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -15.842 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.887 | Likely Pathogenic | 0.0733 | 0.5269 | 3.53 | Destabilizing | 1.8 | 0.43 | Likely Benign | 1.98 | Ambiguous | 0.66 | Ambiguous | -5.14 | Deleterious | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.2617A>G | S873G 2D AIThe SynGAP1 missense variant S873G is catalogued in gnomAD (ID 6‑33443169‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | 6-33443169-A-G | 4 | 2.48e-6 | -5.702 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.120 | Likely Benign | 0.2897 | 0.5270 | -1.88 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.364C>A | P122T 2D AIThe SynGAP1 missense variant P122T 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 P122T 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 | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.954 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.186 | Likely Benign | 0.2068 | 0.5270 | -1.43 | Neutral | 0.580 | Possibly Damaging | 0.185 | Benign | 4.19 | Benign | 0.13 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.2429G>T | R810L 2D AIThe SynGAP1 R810L missense change is not reported in ClinVar and is absent from 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 outcome. 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 effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic impact for R810L. 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.172 | In-Between | 0.834 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | 0.2019 | 0.5271 | -4.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.362C>G | A121G 2D AIThe SynGAP1 missense variant A121G is catalogued in gnomAD (ID 6‑33432227‑C‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the evidence strongly supports a benign effect for A121G, and this conclusion does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | 6-33432227-C-G | 4 | 2.48e-6 | -3.123 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 0.2407 | 0.5271 | -0.52 | Neutral | 0.118 | Benign | 0.026 | Benign | 4.06 | Benign | 0.07 | Tolerated | 3.61 | 5 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.430A>C | T144P 2D AIThe SynGAP1 missense variant T144P 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. 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, 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 predictions and the consensus call indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | -11.920 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 0.159 | Likely Benign | 0.2508 | 0.5271 | -2.66 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.76 | Benign | 0.00 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| c.3649G>A | E1217K 2D AIThe SynGAP1 missense variant E1217K is not reported in ClinVar and is absent from gnomAD. 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 the 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 points to a pathogenic effect. 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 | 0.599170 | Disordered | 0.493043 | Uncertain | 0.877 | 0.563 | 0.250 | -12.869 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.306 | Likely Benign | 0.1826 | 0.5272 | -3.09 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.1400A>T | D467V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467V missense variant is not reported in ClinVar or gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta and premPS, while the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. Two tools, FoldX and Foldetta, give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect, 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. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -15.041 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.893 | Likely Pathogenic | 0.0644 | 0.5274 | 1.24 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.66 | Ambiguous | 0.02 | Likely Benign | -8.70 | Deleterious | 0.997 | Probably Damaging | 0.997 | Probably Damaging | -1.28 | Pathogenic | 0.02 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| 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 | 0.131 | Likely Benign | 0.1310 | 0.5275 | -0.31 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.36 | Likely Benign | 0.23 | Likely Benign | -2.46 | Neutral | 0.975 | Probably Damaging | 0.969 | Probably Damaging | 2.46 | Pathogenic | 0.15 | Tolerated | 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 | 0.131 | Likely Benign | 0.1310 | 0.5275 | -0.31 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.36 | Likely Benign | 0.23 | Likely Benign | -2.46 | Neutral | 0.975 | Probably Damaging | 0.969 | Probably Damaging | 2.46 | Pathogenic | 0.15 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| 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 | 0.1805 | 0.5276 | -1.99 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.60 | Benign | 0.30 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3341G>T | S1114I 2D AIThe SynGAP1 missense variant S1114I is reported in gnomAD (ID 6‑33443893‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443893-G-T | -6.718 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.023 | Likely Benign | 0.1159 | 0.5276 | -1.86 | Neutral | 0.570 | Possibly Damaging | 0.292 | Benign | 2.65 | Benign | 0.02 | Affected | 4.32 | 2 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||
| 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 | 0.3392 | 0.5279 | -2.69 | Deleterious | 0.112 | Benign | 0.061 | Benign | 2.53 | Benign | 0.02 | Affected | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||
| c.1690G>A | E564K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E564K is not reported in ClinVar and is present in the gnomAD database (variant ID 6‑33440742‑G‑A). Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only SIFT predicts a benign outcome. Uncertain results are reported by FoldX, Foldetta, 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 pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence supports a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023534 | Structured | 0.038418 | Uncertain | 0.891 | 0.208 | 0.000 | 6-33440742-G-A | -15.834 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.854 | Likely Pathogenic | 0.1988 | 0.5280 | 0.76 | Ambiguous | 0.1 | 2.06 | Destabilizing | 1.41 | Ambiguous | 0.89 | Ambiguous | -3.95 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | -1.35 | Pathogenic | 0.10 | Tolerated | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||
| c.2654C>A | P885H 2D AIThe SynGAP1 missense variant P885H is not reported in ClinVar and is absent from 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) 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 evidence, including the high‑accuracy tools, 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 | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -5.239 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.083 | Likely Benign | 0.1552 | 0.5280 | -1.68 | Neutral | 0.938 | Possibly Damaging | 0.749 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.2911C>G | P971A 2D AIThe SynGAP1 missense variant P971A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this 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 | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | -4.244 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.3100 | 0.5282 | -0.51 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.05 | Benign | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3097T>G | S1033A 2D AIThe SynGAP1 missense variant S1033A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions indicates that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.107 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.4387 | 0.5282 | 0.06 | Neutral | 0.220 | Benign | 0.085 | Benign | 2.81 | Benign | 1.00 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.1103C>A | P368Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P368Q 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. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Remaining tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of definitive predictions (five pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.363090 | Structured | 0.439989 | Uncertain | 0.580 | 0.677 | 0.250 | -6.019 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.205 | Likely Benign | 0.1694 | 0.5283 | 1.56 | Ambiguous | 0.8 | 1.71 | Ambiguous | 1.64 | Ambiguous | 0.71 | Ambiguous | -5.10 | Deleterious | 0.991 | Probably Damaging | 0.881 | Possibly Damaging | 1.71 | Pathogenic | 0.04 | Affected | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||
| 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 | 0.1168 | 0.5283 | -2.28 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.61 | Benign | 0.04 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3845A>G | E1282G 2D AIThe SynGAP1 missense variant E1282G is reported in gnomAD (ID 6‑33447893‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, 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. Taken together, the overwhelming majority of predictions support a benign impact, and there is no ClinVar classification to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447893-A-G | -2.649 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.219 | Likely Benign | 0.2729 | 0.5284 | -1.25 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.68 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.698G>A | C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y 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 Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate 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 | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.893 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.904 | Likely Pathogenic | 0.1324 | 0.5284 | 13.15 | Destabilizing | 4.6 | 0.04 | Likely Benign | 6.60 | Destabilizing | 0.71 | Ambiguous | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 4.29 | 391 | 0 | -2 | -3.8 | 60.04 | 248.9 | -63.0 | 0.0 | 0.3 | 0.0 | 0.4 | X | X | Potentially Pathogenic | The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.3515A>T | H1172L 2D AIThe SynGAP1 missense variant H1172L 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. 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, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for H1172L, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -0.545 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.426 | Likely Benign | 0.0815 | 0.5285 | -2.30 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.47 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||
| c.569G>A | S190N 2D AIThe SynGAP1 missense variant S190N is not 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, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The remaining tools, ESM1b and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign (two benign votes versus one pathogenic and one uncertain); and Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -7.497 | In-Between | 0.838 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | 0.1119 | 0.5285 | -1.73 | Neutral | 0.759 | Possibly Damaging | 0.202 | Benign | 4.06 | Benign | 0.08 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.389A>T | Q130L 2D AIThe SynGAP1 missense variant Q130L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q130L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.643 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.0975 | 0.5286 | -1.63 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.11 | Benign | 0.02 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.2467A>G | S823G 2D AIThe SynGAP1 missense variant S823G 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 (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the Foldetta stability analysis is unavailable. 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 | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.034 | Likely Benign | 0.822 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | 0.2855 | 0.5287 | -2.59 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.96 | Pathogenic | 0.00 | Affected | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3452C>A | S1151Y 2D AIThe SynGAP1 missense variant S1151Y is not 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, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. AlphaMissense‑Optimized also 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 high‑confidence tools and the consensus prediction favor a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -4.456 | Likely Benign | 0.642 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | 0.0778 | 0.5287 | -0.87 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.68 | Benign | 0.05 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.527G>T | S176I 2D AIThe SynGAP1 missense variant S176I is not 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 FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑vs‑2 split, and Foldetta results are not available. Overall, the majority of evidence (six benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, 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. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -10.247 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.152 | Likely Benign | 0.0790 | 0.5290 | -2.03 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.04 | Benign | 0.06 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.590A>C | E197A 2D AIThe SynGAP1 E197A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta (which would combine FoldX‑MD and Rosetta outputs) has no available result. Overall, the balance of evidence—including the pathogenic majority in the high‑accuracy consensus—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -7.956 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.3134 | 0.5290 | -3.56 | Deleterious | 0.055 | Benign | 0.016 | Benign | 4.06 | Benign | 0.02 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.80C>A | P27H 2D AIThe SynGAP1 missense variant P27H is not 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 P27H, 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 | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -4.116 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.2384 | 0.5290 | -2.46 | Neutral | 0.992 | Probably Damaging | 0.977 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.1313C>T | A438V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (gnomAD ID 6‑33438218‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive (Uncertain). Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | 6-33438218-C-T | 3 | 1.86e-6 | 1.405 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.0904 | 0.5292 | -0.36 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.53 | Ambiguous | -1.21 | Stabilizing | 1.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.45 | Benign | 0.97 | Tolerated | 3.38 | 26 | 0 | 0 | 2.4 | 28.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||
| c.699T>G | C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.899 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.772 | Likely Pathogenic | 0.1727 | 0.5292 | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.932A>T | H311L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311L missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. Tools that predict a pathogenic outcome are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -10.119 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.663 | Likely Pathogenic | 0.0961 | 0.5292 | -0.53 | Ambiguous | 0.0 | -0.04 | Likely Benign | -0.29 | Likely Benign | 0.43 | Likely Benign | -7.99 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.87 | Pathogenic | 0.02 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.2989G>C | A997P 2D AIThe SynGAP1 missense variant A997P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -2.014 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.1938 | 0.5294 | -1.17 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.11 | Benign | 0.00 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1896 | 0.5294 | -0.74 | Neutral | 0.995 | Probably Damaging | 0.940 | Probably Damaging | 2.48 | Pathogenic | 0.25 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.1111A>G | S371G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371G is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -2.073 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.164 | Likely Benign | 0.3192 | 0.5295 | 0.47 | Likely Benign | 0.3 | 0.49 | Likely Benign | 0.48 | Likely Benign | 0.35 | Likely Benign | -1.32 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.63 | Benign | 0.17 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.2063A>C | E688A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Foldetta, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity; 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 combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of evidence points to a pathogenic effect for E688A. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -13.556 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.495 | Likely Benign | 0.3806 | 0.5296 | 0.55 | Ambiguous | 0.5 | -0.53 | Ambiguous | 0.01 | Likely Benign | 0.68 | Ambiguous | -5.55 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.2947A>T | S983C 2D AIThe SynGAP1 missense variant S983C 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 and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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, and PROVEAN) indicates a likely pathogenic effect. 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 impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -7.083 | In-Between | 0.741 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | 0.1657 | 0.5298 | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3118G>A | G1040S 2D AIThe SynGAP1 missense variant G1040S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence (six benign versus four pathogenic predictions) points to a benign impact for G1040S. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.179 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.653 | Likely Pathogenic | 0.2332 | 0.5298 | -1.81 | Neutral | 0.827 | Possibly Damaging | 0.375 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.1597G>C | A533P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only FATHMM predicts pathogenic. Stability‑based methods are inconclusive: FoldX, Rosetta, and the combined Foldetta output are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as unavailable. Overall, the consensus of the majority of tools indicates a benign impact. This prediction does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.951 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.187 | Likely Benign | 0.1925 | 0.5299 | -0.93 | Ambiguous | 0.3 | -0.92 | Ambiguous | -0.93 | Ambiguous | -0.18 | Likely Benign | -0.48 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.26 | Pathogenic | 0.09 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| 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 | 0.0992 | 0.5299 | -3.30 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.1996G>A | E666K 2D AIThe SynGAP1 missense variant E666K is not 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, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, 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 | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -11.367 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.401 | Likely Benign | 0.2953 | 0.5300 | 0.20 | Likely Benign | 0.6 | 0.30 | Likely Benign | 0.25 | Likely Benign | 0.43 | Likely Benign | -3.26 | Deleterious | 0.992 | Probably Damaging | 0.717 | Possibly Damaging | 3.46 | Benign | 0.05 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| 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 | 0.2675 | 0.5300 | -0.07 | Neutral | 0.022 | Benign | 0.008 | Benign | 2.53 | Benign | 0.11 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.3034C>T | P1012S 2D AIThe SynGAP1 missense variant P1012S is catalogued in gnomAD (ID 6‑33443586‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | 6-33443586-C-T | 2 | 1.24e-6 | -3.342 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.3217 | 0.5300 | -0.23 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.81 | Benign | 0.22 | Tolerated | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3181G>A | G1061S 2D AIThe SynGAP1 missense variant G1061S is listed in ClinVar (ID 3571724.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods supports a benign classification for G1061S, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | Uncertain | 1 | -4.891 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.283 | Likely Benign | 0.2404 | 0.5300 | -0.68 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.00 | Benign | 0.00 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3376G>A | G1126S 2D AIThe SynGAP1 missense variant G1126S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1126S, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -5.004 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.268 | Likely Benign | 0.2509 | 0.5300 | -0.28 | Neutral | 0.611 | Possibly Damaging | 0.171 | Benign | 4.78 | Benign | 0.74 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.694G>T | A232S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Across the evaluated in‑silico predictors, all tools except AlphaMissense‑Default converge on a benign interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict benign. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -3.264 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.378 | Likely Benign | 0.2777 | 0.5300 | 0.23 | Likely Benign | 0.1 | -0.23 | Likely Benign | 0.00 | Likely Benign | -0.20 | Likely Benign | 0.54 | Neutral | 0.057 | Benign | 0.025 | Benign | 5.95 | Benign | 1.00 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| 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 | 0.1417 | 0.5303 | -2.56 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1694 | 0.5304 | 0.09 | Neutral | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.548A>T | H183L 2D AIThe SynGAP1 missense variant H183L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign votes). AlphaMissense‑Optimized alone also 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, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -12.898 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.325 | Likely Benign | 0.0911 | 0.5304 | -8.12 | Deleterious | 0.421 | Benign | 0.058 | Benign | 3.79 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.2782C>A | Q928K 2D AIThe SynGAP1 missense variant Q928K has no ClinVar entry and is not reported in gnomAD. 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, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. High‑accuracy evidence therefore consists of an uncertain AlphaMissense‑Optimized score, a Likely Pathogenic SGM‑Consensus, and an unavailable Foldetta prediction. Overall, the majority of tools predict pathogenicity, and there is no ClinVar status to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.986260 | Binding | 0.324 | 0.852 | 0.250 | -4.941 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.259 | Likely Benign | 0.1728 | 0.5306 | -2.80 | Deleterious | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.60 | Pathogenic | 0.00 | Affected | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.4013G>T | R1338L 2D AIThe SynGAP1 missense variant R1338L is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451887‑G‑T). 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, 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 benign vs 2 pathogenic) and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The predictions do 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. | 0.775545 | Disordered | 0.977425 | Binding | 0.393 | 0.697 | 1.000 | 6-33451887-G-T | -3.359 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.232 | Likely Benign | 0.2066 | 0.5307 | -3.65 | Deleterious | 0.001 | Benign | 0.001 | Benign | 3.78 | Benign | 0.01 | Affected | 3.77 | 5 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||
| c.703T>C | S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective 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 | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | Likely Pathogenic | 1 | -14.857 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.870 | Likely Pathogenic | 0.2432 | 0.5307 | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | ||||||||||||
| c.3994A>C | T1332P 2D AIThe SynGAP1 missense variant T1332P is not 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 (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is tied 2‑2 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 existing ClinVar status because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | -3.404 | Likely Benign | 0.918 | Likely Pathogenic | Ambiguous | 0.238 | Likely Benign | 0.2185 | 0.5308 | -3.12 | Deleterious | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.065 | Likely Benign | 0.0852 | 0.5309 | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 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 | 0.065 | Likely Benign | 0.0852 | 0.5309 | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||
| 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 | 0.2499 | 0.5309 | -0.51 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.58 | Benign | 0.35 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.4019C>A | T1340N 2D AIThe SynGAP1 missense variant T1340N is reported in gnomAD (ID 6‑33451893‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T1340N. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451893-C-A | -3.664 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.1755 | 0.5309 | -0.95 | Neutral | 0.092 | Benign | 0.026 | Benign | 4.09 | Benign | 0.02 | Affected | 3.77 | 5 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||
| c.2731G>C | V911L 2D AIThe SynGAP1 missense variant V911L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -2.722 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.1067 | 0.5310 | -0.39 | Neutral | 0.451 | Benign | 0.157 | Benign | 2.73 | Benign | 0.16 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2815C>A | P939T 2D AIThe SynGAP1 missense variant P939T is not 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. High‑accuracy predictions show AlphaMissense‑Optimized as benign, while the SGM Consensus remains inconclusive and Foldetta is unavailable. Overall, more tools (five) predict pathogenicity than benign (four), suggesting the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -5.739 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.139 | Likely Benign | 0.1788 | 0.5310 | -3.34 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.1333G>A | E445K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E445K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic calls arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence—including the high‑accuracy tools—supports a pathogenic effect. This conclusion does not conflict with ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -15.371 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.524 | Likely Pathogenic | 0.1784 | 0.5311 | 0.02 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.02 | Likely Benign | 0.46 | Likely Benign | -3.82 | Deleterious | 0.991 | Probably Damaging | 0.951 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.3160G>A | G1054S 2D AIThe SynGAP1 missense variant G1054S is listed in ClinVar (ID 699126.0) as Benign and is present in gnomAD (variant ID 6‑33443712‑G‑A). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Benign | 1 | 6-33443712-G-A | 32 | 1.99e-5 | -5.294 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.2506 | 0.5311 | 0.21 | Neutral | 0.121 | Benign | 0.013 | Benign | 4.04 | Benign | 0.63 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||
| c.3178G>A | G1060S 2D AIThe SynGAP1 missense variant G1060S is listed in ClinVar with an uncertain significance (ClinVar ID 1512003.0) and is present in gnomAD (variant ID 6‑33443730‑G‑A). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this benign view: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | Uncertain | 1 | 6-33443730-G-A | -4.759 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.376 | Likely Benign | 0.2468 | 0.5311 | -0.08 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.69 | Benign | 0.49 | Tolerated | 4.32 | 2 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||
| c.3358G>A | G1120S 2D AIThe SynGAP1 missense variant G1120S is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that G1120S is most likely benign, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -4.959 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.286 | Likely Benign | 0.2515 | 0.5311 | -0.27 | Neutral | 0.451 | Benign | 0.209 | Benign | 3.69 | Benign | 0.77 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3310C>G | P1104A 2D AIThe SynGAP1 missense variant P1104A 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 indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.677 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.3289 | 0.5315 | -0.54 | Neutral | 0.409 | Benign | 0.184 | Benign | 2.74 | Benign | 0.22 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.2897A>T | H966L 2D AIThe SynGAP1 missense variant H966L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No pathogenic predictions are present among the evaluated algorithms. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) reports likely benign. Foldetta results are not available for this variant. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.974672 | Binding | 0.378 | 0.879 | 0.750 | -6.119 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.183 | Likely Benign | 0.1514 | 0.5316 | -1.74 | Neutral | 0.174 | Benign | 0.062 | Benign | 4.05 | Benign | 0.35 | Tolerated | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.1850A>C | E617A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617A is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Rosetta and Foldetta are uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -8.704 | Likely Pathogenic | 0.769 | Likely Pathogenic | Likely Benign | 0.627 | Likely Pathogenic | 0.3033 | 0.5317 | 0.37 | Likely Benign | 0.1 | 0.89 | Ambiguous | 0.63 | Ambiguous | 0.18 | Likely Benign | -4.75 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| 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 | 0.2438 | 0.5318 | -1.68 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.58 | Benign | 0.00 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.1732G>C | E578Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E578Q missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors indicates a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized, and Foldetta all predict benign. Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic. Foldetta, a protein‑folding stability method, also predicts benign. Overall, the majority of tools, including the high‑accuracy AlphaMissense‑Optimized and Foldetta, support a benign classification, and this is consistent with the lack of ClinVar evidence. 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. | GAP | 0.059222 | Structured | 0.020971 | Uncertain | 0.902 | 0.240 | 0.000 | -9.771 | Likely Pathogenic | 0.491 | Ambiguous | Likely Benign | 0.353 | Likely Benign | 0.1000 | 0.5319 | 0.01 | Likely Benign | 0.1 | -0.12 | Likely Benign | -0.06 | Likely Benign | -0.16 | Likely Benign | -1.21 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.40 | Pathogenic | 0.36 | Tolerated | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.1928A>G | E643G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default; FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta’s stability prediction is uncertain. Overall, the majority of reliable tools predict pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.503 | Likely Pathogenic | 0.707 | Likely Pathogenic | Likely Benign | 0.520 | Likely Pathogenic | 0.2821 | 0.5319 | 1.45 | Ambiguous | 0.3 | 2.06 | Destabilizing | 1.76 | Ambiguous | 1.01 | Destabilizing | -6.81 | Deleterious | 0.983 | Probably Damaging | 0.390 | Benign | 2.94 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.3424T>G | S1142A 2D AIThe SynGAP1 missense variant S1142A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) confirms a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S1142A 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 | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -3.694 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.4689 | 0.5319 | -1.31 | Neutral | 0.002 | Benign | 0.015 | Benign | 2.73 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3451T>C | S1151P 2D AIThe SynGAP1 missense variant S1151P 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 methods further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that the variant is 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.031 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.123 | Likely Benign | 0.1953 | 0.5320 | -1.47 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.67 | Benign | 0.11 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3590A>T | E1197V 2D AIThe SynGAP1 missense variant E1197V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Overall, the balance of evidence (five pathogenic versus three benign predictions, with one uncertain) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -6.298 | Likely Benign | 0.923 | Likely Pathogenic | Ambiguous | 0.472 | Likely Benign | 0.0440 | 0.5320 | -3.28 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.40 | Benign | 0.03 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.2204G>C | S735T 2D AIThe SynGAP1 missense variant S735T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -5.340 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.1464 | 0.5321 | -1.03 | Neutral | 0.980 | Probably Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.46 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3199C>G | P1067A 2D AIThe SynGAP1 missense variant P1067A 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, representing the sole 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 also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for P1067A, 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.639 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 0.3097 | 0.5322 | -2.05 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.87 | Benign | 0.07 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1189 | 0.5323 | -2.42 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2746G>C | V916L 2D AIThe SynGAP1 missense variant V916L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.645 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.1190 | 0.5323 | 0.31 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.73 | Benign | 0.09 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1030G>A | G344S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344S is listed in ClinVar (ID 981240.0) as Pathogenic and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic; the only inconclusive result is premPS, which is marked Uncertain. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | Pathogenic | 5 | -11.254 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.790 | Likely Pathogenic | 0.2735 | 0.5324 | 9.02 | Destabilizing | 0.7 | 6.08 | Destabilizing | 7.55 | Destabilizing | 0.98 | Ambiguous | -5.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.45 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 1 | 0 | -0.4 | 30.03 | 217.3 | -51.7 | 0.0 | 0.1 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Because Gly344 lacks a proper side chain, it allows the anti-parallel β sheet strand (res. Gly341-Pro349) to have a slight twist. Within a β strand, side chains normally alternate between outward and inward positions, but glycine is an exception as it allows the alternating pattern to skip a residue. Introducing serine or any other residue with a side chain at position 344 prevents this unique skip in the alternating pattern, causing structural strain or likely preventing correct folding altogether. Additionally, Tyr342 shields Gly344 from the solvent, contributing to twist formation in the β sheet and stabilizing the β-strand.In the variant simulations, the side chain of Ser344 assumes the inward position. However, the hydrophobic niche formed by multiple C2 domain residues (e.g., Val365, Val343, Leu327) is not accommodating for its hydroxyl group. The outward position, not seen in the simulations, would be equally disadvantageous due to the presence of hydrophobic residues on that side as well (e.g., Leu345, Tyr342). Serine is also not well-suited for twist formation, as it tends to suppress twisting and bending in β sheets. At this position, the hydroxyl group of Ser344 could also form hydrogen bonds with the backbone atoms of the Gly-rich Ω loop in the C2 domain (e.g., Thr366, Leu367, Gly378; res. Pro364-Pro398), potentially adversely affecting membrane-loop dynamics and ultimately compromising the stability of the SynGAP-membrane association. | |||||||||||
| c.3238G>C | A1080P 2D AIThe SynGAP1 missense variant A1080P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A1080P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -2.429 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.170 | Likely Benign | 0.1884 | 0.5324 | -1.15 | Neutral | 0.996 | Probably Damaging | 0.833 | Possibly Damaging | 3.96 | Benign | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.2029A>G | S677G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and premPS—are treated as unavailable. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the evidence supports a benign classification for S677G, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -5.126 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.126 | Likely Benign | 0.2885 | 0.5325 | 0.98 | Ambiguous | 0.1 | 1.20 | Ambiguous | 1.09 | Ambiguous | 0.64 | Ambiguous | -1.38 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.30 | Benign | 0.26 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.908G>C | G303A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is uncertain. Overall, the variant is most likely benign based on the consensus of predictive tools, 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 Benign | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -1.965 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 0.3724 | 0.5325 | 1.66 | Ambiguous | 0.2 | -0.51 | Ambiguous | 0.58 | Ambiguous | 0.10 | Likely Benign | -0.90 | Neutral | 0.112 | Benign | 0.058 | Benign | 4.07 | Benign | 0.35 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| 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 | 0.1161 | 0.5326 | -1.28 | Neutral | 0.901 | Possibly Damaging | 0.535 | Possibly Damaging | 2.56 | Benign | 0.36 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.401G>C | S134T 2D AIThe SynGAP1 missense variant S134T is listed in gnomAD (ID 6‑33432698‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion is not contradicted by ClinVar, which contains no classification for S134T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | 6-33432698-G-C | 1 | 6.32e-7 | -5.187 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.069 | Likely Benign | 0.1083 | 0.5326 | -1.76 | Neutral | 0.034 | Benign | 0.047 | Benign | 3.85 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.109T>C | S37P 2D AIThe SynGAP1 missense variant S37P 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 S37P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -3.788 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.156 | Likely Benign | 0.2657 | 0.5327 | -1.29 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.2471G>A | S824N 2D AIThe SynGAP1 missense variant S824N is reported in gnomAD (6‑33443023‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | 6-33443023-G-A | 2 | 1.24e-6 | -4.473 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.1713 | 0.5327 | -1.08 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.61 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.566C>A | P189H 2D AIThe SynGAP1 missense variant P189H is not 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 remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 P189H 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 | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -9.633 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.298 | Likely Benign | 0.1620 | 0.5327 | -6.49 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.883A>C | T295P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -9.941 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.531 | Likely Pathogenic | 0.2442 | 0.5327 | 0.26 | Likely Benign | 0.2 | 3.30 | Destabilizing | 1.78 | Ambiguous | 0.60 | Ambiguous | -4.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.3509G>T | S1170I 2D AIThe SynGAP1 missense variant S1170I is 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, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and 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, the SGM‑Consensus (majority vote) also predicts benign, and the Foldetta protein‑folding stability analysis is unavailable. Taken together, the preponderance of high‑confidence predictions indicates that 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 | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -3.813 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.600 | Likely Pathogenic | 0.0754 | 0.5329 | -2.16 | Neutral | 0.998 | Probably Damaging | 0.990 | Probably Damaging | 5.29 | Benign | 0.01 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||
| c.3119G>C | G1040A 2D AIThe SynGAP1 missense variant G1040A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic). 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 conclusion does not contradict any ClinVar annotation, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.625 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.606 | Likely Pathogenic | 0.3246 | 0.5331 | -1.65 | Neutral | 0.114 | Benign | 0.030 | Benign | -0.74 | Pathogenic | 0.30 | Tolerated | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3266G>C | G1089A 2D AIThe SynGAP1 missense variant G1089A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -2.864 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.142 | Likely Benign | 0.3475 | 0.5331 | -1.73 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.45 | Pathogenic | 0.02 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1768A>T | S590C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S590C has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split assessment: benign predictions come from FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. The high‑accuracy subset indicates that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both support a pathogenic or neutral outcome, respectively. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns with the SGM‑Consensus designation. Because there is no ClinVar classification, the predictions do not contradict existing clinical data. Thus, based on the available computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -10.823 | Likely Pathogenic | 0.698 | Likely Pathogenic | Likely Benign | 0.631 | Likely Pathogenic | 0.1094 | 0.5332 | -0.09 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.13 | Likely Benign | 0.56 | Ambiguous | -4.48 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 3.08 | Benign | 0.07 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| 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 | 0.2130 | 0.5332 | 1.09 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.64 | Benign | 0.24 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3377G>C | G1126A 2D AIThe SynGAP1 missense variant G1126A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -6.402 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.228 | Likely Benign | 0.3505 | 0.5333 | -0.63 | Neutral | 0.124 | Benign | 0.061 | Benign | 4.83 | Benign | 0.56 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.913A>C | T305P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (7 pathogenic vs. 5 benign) lean toward a pathogenic impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -5.203 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.293 | Likely Benign | 0.2206 | 0.5333 | 3.64 | Destabilizing | 1.1 | 6.02 | Destabilizing | 4.83 | Destabilizing | 0.71 | Ambiguous | -2.83 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.72 | Pathogenic | 0.06 | Tolerated | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||
| c.1051G>T | A351S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (integrating FoldX‑MD and Rosetta)—all report benign or likely benign. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely benign; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.823 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.016 | Likely Benign | 0.2558 | 0.5334 | 0.24 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.25 | Likely Benign | 0.27 | Likely Benign | -1.42 | Neutral | 0.080 | Benign | 0.023 | Benign | 1.88 | Pathogenic | 0.13 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1597G>T | A533S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A533S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains all tools except FATHMM, which stands alone in the pathogenic group. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign effect. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.179055 | Structured | 0.026324 | Uncertain | 0.843 | 0.393 | 0.000 | -3.740 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.193 | Likely Benign | 0.2612 | 0.5334 | 0.24 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.10 | Likely Benign | -0.14 | Likely Benign | 0.33 | Neutral | 0.009 | Benign | 0.039 | Benign | -1.14 | Pathogenic | 0.45 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.571A>G | S191G 2D AIThe SynGAP1 missense variant S191G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also leans toward benign (two benign versus two uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S191G is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.161 | In-Between | 0.506 | Ambiguous | Likely Benign | 0.173 | Likely Benign | 0.2893 | 0.5335 | -2.43 | Neutral | 0.131 | Benign | 0.058 | Benign | 3.77 | Benign | 0.03 | Affected | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.286G>A | G96S 2D AIThe SynGAP1 missense variant G96S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33425894‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | Uncertain | 1 | 6-33425894-G-A | 5 | 3.10e-6 | -3.049 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.3001 | 0.5336 | -0.76 | Neutral | 0.364 | Benign | 0.008 | Benign | 4.25 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||
| c.85A>C | M29L 2D AIThe SynGAP1 missense variant M29L is not 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 | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -1.633 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.200 | Likely Benign | 0.1984 | 0.5336 | -0.49 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.27 | Benign | 0.00 | Affected | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.85A>T | M29L 2D AIThe SynGAP1 missense variant M29L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -1.633 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.200 | Likely Benign | 0.1984 | 0.5336 | -0.49 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.27 | Benign | 0.00 | Affected | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2866T>C | S956P 2D AIThe SynGAP1 missense variant S956P 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, 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 | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -3.526 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.157 | Likely Benign | 0.2670 | 0.5337 | -0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 1.95 | Pathogenic | 0.05 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.2432C>A | P811Q 2D AIThe SynGAP1 missense variant P811Q is not 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. 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 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 | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.145 | Likely Benign | 0.431 | Ambiguous | Likely Benign | 0.138 | Likely Benign | 0.1523 | 0.5338 | -2.38 | Neutral | 0.982 | Probably Damaging | 0.875 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||
| c.2873A>T | H958L 2D AIThe SynGAP1 missense variant H958L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, SIFT and ESM1b, predict a pathogenic outcome. When the high‑accuracy consensus is considered, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely benign verdict, and AlphaMissense‑Optimized also reports benign. Foldetta predictions are unavailable. Overall, the majority of evidence supports a benign interpretation, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict existing ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.976011 | Binding | 0.371 | 0.913 | 0.750 | -8.422 | Likely Pathogenic | 0.087 | Likely Benign | Likely Benign | 0.181 | Likely Benign | 0.1723 | 0.5338 | -1.28 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.25 | Benign | 0.03 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.2894A>T | H965L 2D AIThe SynGAP1 missense variant H965L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect. Benign predictors include REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool in the dataset returned a pathogenic prediction. Consensus predictors such as SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classify the variant as Likely Benign. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus is Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.978700 | Binding | 0.342 | 0.882 | 0.750 | -6.708 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.1606 | 0.5338 | -1.66 | Neutral | 0.033 | Benign | 0.018 | Benign | 4.06 | Benign | 1.00 | Tolerated | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.391G>A | G131S 2D AIThe SynGAP1 missense variant G131S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -2.953 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.2823 | 0.5338 | -2.75 | Deleterious | 0.115 | Benign | 0.026 | Benign | 4.10 | Benign | 0.02 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3757G>A | A1253T 2D AISynGAP1 missense variant A1253T is predicted to be benign by all evaluated in‑silico tools. The consensus group of predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—uniformly classify the change as benign, with no tool indicating pathogenicity. High‑accuracy methods corroborate this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also labels the variant as likely benign. Foldetta stability analysis is unavailable. ClinVar contains no entry for this variant, and it is not present in gnomAD. Overall, the predictive evidence strongly supports a benign classification, consistent with the lack of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -4.116 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.1016 | 0.5339 | -0.08 | Neutral | 0.042 | Benign | 0.061 | Benign | 2.79 | Benign | 0.41 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.83C>T | S28F 2D AIThe SynGAP1 missense variant S28F is not 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, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. 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; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.548 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.045 | Likely Benign | 0.0748 | 0.5340 | -1.13 | Neutral | 0.009 | Benign | 0.002 | Benign | 4.13 | Benign | 0.05 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.2524T>C | S842P 2D AIThe SynGAP1 missense variant S842P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity largely agree: 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 deleterious effect. Only REVEL classifies the variant as benign. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that S842P is most likely pathogenic, 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 Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | -13.890 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.309 | Likely Benign | 0.1494 | 0.5342 | -3.43 | Deleterious | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 1.99 | Pathogenic | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.3444 | 0.5342 | -1.15 | Neutral | 0.798 | Possibly Damaging | 0.433 | Benign | 2.58 | Benign | 0.50 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.574G>A | A192T 2D AIThe SynGAP1 missense variant A192T has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.562 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | 0.1148 | 0.5343 | -2.46 | Neutral | 0.978 | Probably Damaging | 0.714 | Possibly Damaging | 3.96 | Benign | 0.34 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.2882A>T | H961L 2D AIThe SynGAP1 missense variant H961L is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT and ESM1b predict pathogenicity, but these are outliers among the consensus. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and 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 the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.989835 | Disordered | 0.984562 | Binding | 0.323 | 0.893 | 0.750 | -8.547 | Likely Pathogenic | 0.109 | Likely Benign | Likely Benign | 0.155 | Likely Benign | 0.1465 | 0.5344 | -1.21 | Neutral | 0.144 | Benign | 0.078 | Benign | 4.13 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.3407A>C | Q1136P 2D AIThe SynGAP1 missense variant Q1136P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.067 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.364 | Likely Benign | 0.2188 | 0.5344 | -1.06 | Neutral | 0.961 | Probably Damaging | 0.745 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.2968T>C | S990P 2D AIThe SynGAP1 missense variant S990P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. 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 | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -3.150 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.1910 | 0.5345 | -1.95 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.74 | Benign | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1470 | 0.5345 | -2.03 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||
| c.1036G>C | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors and the SGM‑Consensus support a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.384 | Likely Benign | 0.1237 | 0.5348 | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1036G>T | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.386 | Likely Benign | 0.1237 | 0.5348 | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.3650A>T | E1217V 2D AIThe SynGAP1 missense variant E1217V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: REVEL scores the variant as benign, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenicity. Grouping by consensus, the majority of tools (seven) support a pathogenic effect, while only one tool (REVEL) indicates benign. High‑accuracy assessments further reinforce a deleterious interpretation: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic, and AlphaMissense‑Optimized remains uncertain. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the computational evidence overwhelmingly suggests that E1217V is pathogenic, a finding that aligns with its lack of ClinVar annotation and gnomAD presence. Thus, the variant is most likely pathogenic, and this prediction is consistent with its absence from ClinVar and gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.599170 | Disordered | 0.493043 | Uncertain | 0.877 | 0.563 | 0.250 | -12.098 | Likely Pathogenic | 0.843 | Likely Pathogenic | Ambiguous | 0.351 | Likely Benign | 0.0579 | 0.5348 | -5.48 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||
| c.3232G>C | V1078L 2D AIThe SynGAP1 missense variant V1078L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that V1078L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.547 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.091 | Likely Benign | 0.0889 | 0.5349 | -0.16 | Neutral | 0.451 | Benign | 0.209 | Benign | 4.13 | Benign | 0.56 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3416A>C | Q1139P 2D AIThe SynGAP1 missense variant Q1139P 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. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments 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 indicates 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 | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.753 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.437 | Likely Benign | 0.2199 | 0.5349 | -1.74 | Neutral | 0.812 | Possibly Damaging | 0.396 | Benign | 5.28 | Benign | 0.00 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.1039A>C | T347P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T347P variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -9.323 | Likely Pathogenic | 0.417 | Ambiguous | Likely Benign | 0.236 | Likely Benign | 0.2000 | 0.5350 | 0.55 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.42 | Likely Benign | 0.65 | Ambiguous | -2.41 | Neutral | 0.627 | Possibly Damaging | 0.139 | Benign | 1.63 | Pathogenic | 0.12 | Tolerated | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||
| c.2434C>G | P812A 2D AIThe SynGAP1 missense variant P812A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign 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 | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.113 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.137 | Likely Benign | 0.3555 | 0.5350 | -1.49 | Neutral | 0.989 | Probably Damaging | 0.869 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.325A>T | S109C 2D AIThe SynGAP1 missense variant S109C is not 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, SIFT, 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 Benign and the SGM‑Consensus (majority vote) also as 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 | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -6.268 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.217 | Likely Benign | 0.1084 | 0.5354 | -2.19 | Neutral | 0.983 | Probably Damaging | 0.431 | Benign | 3.46 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3947A>T | N1316I 2D  AIThe SynGAP1 missense variant N1316I is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, 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 benign vs 2 pathogenic). 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 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. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | -4.829 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.147 | Likely Benign | 0.0719 | 0.5354 | -2.86 | Deleterious | 0.009 | Benign | 0.004 | Benign | 3.91 | Benign | 0.00 | Affected | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.3488A>T | H1163L 2D AIThe SynGAP1 missense variant H1163L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, 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) and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward a pathogenic impact. There is no ClinVar entry to contradict this assessment, so 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. | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.401 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.568 | Likely Pathogenic | 0.0938 | 0.5356 | -3.15 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.55 | Benign | 0.10 | Tolerated | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||
| c.3136C>G | P1046A 2D AIThe SynGAP1 missense variant P1046A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443688‑C‑G). 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; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | Uncertain | 1 | 6-33443688-C-G | 1 | 6.20e-7 | -3.246 | Likely Benign | 0.048 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.2976 | 0.5358 | -1.67 | Neutral | 0.001 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.29 | Tolerated | 3.77 | 5 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||
| c.3845A>C | E1282A 2D AIThe SynGAP1 missense variant E1282A is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign impact, and this conclusion does not contradict any ClinVar status, as none exists for E1282A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | -1.980 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.3411 | 0.5358 | 0.52 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.94 | Benign | 0.38 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0947 | 0.5362 | -0.11 | Neutral | 0.761 | Possibly Damaging | 0.399 | Benign | 2.58 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.2958G>C | E986D 2D AIThe SynGAP1 missense variant E986D is not 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign votes) and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. There is no contradiction with ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.001 | Likely Benign | 0.628 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | 0.2081 | 0.5364 | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.2958G>T | E986D 2D AIThe SynGAP1 missense variant E986D is not 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign votes) and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. There is no contradiction with ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.001 | Likely Benign | 0.628 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | 0.2081 | 0.5364 | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1304 | 0.5365 | -1.49 | Neutral | 0.393 | Benign | 0.239 | Benign | 2.56 | Benign | 0.25 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3828C>A | D1276E 2D AIThe SynGAP1 missense variant D1276E is catalogued in gnomAD (ID 6‑33447876‑C‑A) but has no ClinVar submission. Functional prediction tools show a split assessment: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized alone predicts benign, and no Foldetta stability data are available. Overall, the majority of individual predictors favor a benign effect, but the SGM consensus contradicts this by labeling the variant pathogenic. Because ClinVar contains no classification, there is no external evidence to resolve the discrepancy. Thus, based on the current computational evidence, the variant is most likely benign, though the SGM consensus suggests a possible pathogenic interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 6-33447876-C-A | -0.388 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.091 | Likely Benign | 0.1027 | 0.5365 | -2.64 | Deleterious | 0.027 | Benign | 0.020 | Benign | 1.26 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||
| c.3828C>G | D1276E 2D AIThe SynGAP1 missense variant D1276E is not reported in ClinVar and is absent from gnomAD. Consensus from routine in silico predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar), and ESM1b, versus pathogenic calls from PROVEAN, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic. Foldetta, a protein‑folding stability method, has no available output for this residue. Overall, the balance of evidence tilts toward a benign interpretation, and this conclusion is not in conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.388 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.092 | Likely Benign | 0.1027 | 0.5365 | -2.64 | Deleterious | 0.027 | Benign | 0.020 | Benign | 1.26 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.3946A>T | N1316Y 2D  AIThe SynGAP1 missense variant N1316Y is reported in gnomAD (variant ID 6‑33451820‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen2_HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen2_HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is available). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451820-A-T | -5.579 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.101 | Likely Benign | 0.0671 | 0.5365 | -2.48 | Neutral | 0.939 | Possibly Damaging | 0.396 | Benign | 3.90 | Benign | 0.00 | Affected | 3.77 | 5 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||
| c.1153T>G | S385A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385A is catalogued in gnomAD (variant ID 6‑33438058‑T‑G) but has no entry in ClinVar. All available in silico predictors report a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | 6-33438058-T-G | -4.412 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.243 | Likely Benign | 0.4910 | 0.5366 | 0.03 | Likely Benign | 0.1 | 0.19 | Likely Benign | 0.11 | Likely Benign | 0.07 | Likely Benign | -0.28 | Neutral | 0.140 | Benign | 0.355 | Benign | 4.65 | Benign | 0.13 | Tolerated | 4.32 | 3 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||
| 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 | 0.2670 | 0.5366 | -1.22 | Neutral | 0.640 | Possibly Damaging | 0.386 | Benign | 2.63 | Benign | 0.06 | Tolerated | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.1624A>C | N542H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542H is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence supports a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -10.983 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.791 | Likely Pathogenic | 0.1137 | 0.5368 | 0.06 | Likely Benign | 0.1 | -0.12 | Likely Benign | -0.03 | Likely Benign | 0.46 | Likely Benign | -3.91 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.44 | Pathogenic | 0.05 | Affected | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||
| c.2425A>G | S809G 2D AIThe SynGAP1 missense variant S809G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the preponderance of evidence indicates that S809G is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -6.100 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.085 | Likely Benign | 0.2743 | 0.5369 | -1.80 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.61 | Benign | 0.02 | Affected | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| 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 | 0.1299 | 0.5370 | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.04 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3452C>T | S1151F 2D AIThe SynGAP1 missense variant S1151F is 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 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -4.433 | Likely Benign | 0.661 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | 0.0749 | 0.5370 | -0.60 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.70 | Benign | 0.19 | Tolerated | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.2383C>G | P795A 2D AIThe SynGAP1 missense variant P795A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly suggests that P795A is most likely benign, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.972450 | Disordered | 0.410339 | Uncertain | 0.457 | 0.903 | 0.875 | -5.348 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.3672 | 0.5371 | -0.52 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.32 | Benign | 0.16 | Tolerated | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.601G>T | D201Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201Y missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Rosetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus predicts likely pathogenic; Foldetta is uncertain. Because the majority of consensus and individual predictors (seven pathogenic vs four benign) lean toward a damaging outcome, the variant is most likely pathogenic. This assessment is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.916 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.334 | Likely Benign | 0.0431 | 0.5371 | 0.28 | Likely Benign | 0.2 | 2.39 | Destabilizing | 1.34 | Ambiguous | 0.31 | Likely Benign | -4.93 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.02 | Benign | 0.02 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.901G>C | A301P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.808 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.225 | Likely Benign | 0.1907 | 0.5371 | -0.47 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.44 | Likely Benign | 0.40 | Likely Benign | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.2929G>T | A977S 2D AIThe SynGAP1 missense variant A977S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence indicates that A977S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.909 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.2820 | 0.5373 | -0.38 | Neutral | 0.965 | Probably Damaging | 0.702 | Possibly Damaging | 4.02 | Benign | 0.45 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1734 | 0.5373 | -3.51 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.46 | Pathogenic | 0.19 | Tolerated | 3.77 | 5 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||
| c.1922C>T | S641L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to 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. | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -9.501 | Likely Pathogenic | 0.237 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.1248 | 0.5376 | 0.33 | Likely Benign | 0.3 | -0.14 | Likely Benign | 0.10 | Likely Benign | 0.32 | Likely Benign | -4.33 | Deleterious | 0.115 | Benign | 0.014 | Benign | 3.39 | Benign | 0.07 | Tolerated | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||
| c.2376A>C | E792D 2D AIThe SynGAP1 missense variant E792D 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 all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No pathogenic predictions are present. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise predicts likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | -3.746 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.2096 | 0.5376 | -1.06 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.97 | Benign | 0.26 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2376A>T | E792D 2D AIThe SynGAP1 missense variant E792D 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 all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No pathogenic predictions are present. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise predicts likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | -3.746 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.2096 | 0.5376 | -1.06 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.97 | Benign | 0.26 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2965T>A | S989T 2D AIThe SynGAP1 missense variant S989T 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign outcome. No Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -3.995 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.1183 | 0.5377 | -1.48 | Neutral | 0.770 | Possibly Damaging | 0.396 | Benign | 2.66 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.4024G>T | D1342Y 2D AIThe SynGAP1 missense variant D1342Y is reported in gnomAD (6‑33451898‑G‑T) 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). Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | 6-33451898-G-T | -4.108 | Likely Benign | 0.398 | Ambiguous | Likely Benign | 0.095 | Likely Benign | 0.0868 | 0.5377 | -1.34 | Neutral | 0.939 | Possibly Damaging | 0.496 | Possibly Damaging | 3.98 | Benign | 0.01 | Affected | 4.32 | 4 | -3 | -4 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||
| c.2552C>A | P851H 2D AIThe SynGAP1 missense variant P851H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments reinforce this view: 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 | 0.648219 | Disordered | 0.526893 | Binding | 0.347 | 0.819 | 0.625 | -4.730 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.184 | Likely Benign | 0.1577 | 0.5378 | 0.19 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 4.18 | Benign | 0.15 | Tolerated | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.1601C>T | S534F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain results are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; thus the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -10.948 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | 0.313 | Likely Benign | 0.0621 | 0.5379 | -0.03 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.43 | Likely Benign | 0.43 | Likely Benign | -5.09 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||
| c.896G>C | R299P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299P is not reported in ClinVar or gnomAD, indicating no publicly available frequency data. Prediction tools cluster into benign and pathogenic groups: benign predictions include REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b is uncertain. The SGM‑Consensus label is Likely Pathogenic. High‑accuracy tools give a clear signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta also predicts pathogenic. Overall, the predictions strongly favor a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.662 | In-Between | 0.722 | Likely Pathogenic | Likely Benign | 0.295 | Likely Benign | 0.2072 | 0.5379 | 4.10 | Destabilizing | 0.2 | 3.01 | Destabilizing | 3.56 | Destabilizing | 1.19 | Destabilizing | -4.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.68 | Pathogenic | 0.02 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.3289C>G | P1097A 2D AIThe SynGAP1 missense variant P1097A 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), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from 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. Based on the unanimous benign predictions and the lack of any pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -4.315 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.3199 | 0.5381 | -1.77 | Neutral | 0.245 | Benign | 0.140 | Benign | 2.71 | Benign | 0.26 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.1976C>G | S659C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. Two tools (Rosetta and ESM1b) return uncertain results and are not counted as evidence for either side. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. 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. | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -7.133 | In-Between | 0.161 | Likely Benign | Likely Benign | 0.173 | Likely Benign | 0.1130 | 0.5384 | 0.09 | Likely Benign | 0.0 | 0.69 | Ambiguous | 0.39 | Likely Benign | 0.36 | Likely Benign | -4.12 | Deleterious | 0.981 | Probably Damaging | 0.397 | Benign | 3.36 | Benign | 0.04 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.3497C>T | A1166V 2D AIThe SynGAP1 A1166V missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Thus, based on current computational predictions, the A1166V variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -4.305 | Likely Benign | 0.843 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | 0.0967 | 0.5384 | -1.04 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 5.43 | Benign | 0.40 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.3715G>A | A1239T 2D AIThe SynGAP1 missense variant A1239T is not reported in ClinVar and has no gnomAD entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the consensus score from SGM‑Consensus is “Likely Benign.” In contrast, two sequence‑based predictors flag it as pathogenic: SIFT and FATHMM. When considering the high‑accuracy subset, AlphaMissense‑Optimized remains benign and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a benign outcome; Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.534779 | Binding | 0.887 | 0.542 | 0.250 | -3.570 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.030 | Likely Benign | 0.0957 | 0.5384 | -1.62 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.37 | Pathogenic | 0.00 | Affected | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.65G>A | R22K 2D  AIThe SynGAP1 missense variant R22K is reported in gnomAD (variant ID 6‑33420329‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for R22K, 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 | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420329-G-A | -4.736 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.032 | Likely Benign | 0.6413 | 0.5384 | Strenghten | -0.12 | Neutral | 0.140 | Benign | 0.067 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 3 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||
| c.1457A>G | E486G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E486G missense change is not listed in ClinVar and has no gnomAD entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM. Those that predict a damaging outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points toward a pathogenic effect. 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 | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -12.488 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 0.328 | Likely Benign | 0.2918 | 0.5385 | 1.09 | Ambiguous | 0.1 | 1.59 | Ambiguous | 1.34 | Ambiguous | -0.14 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.80 | Benign | 0.40 | Tolerated | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| 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 | 0.2285 | 0.5385 | -2.08 | Neutral | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 2.64 | Benign | 0.26 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.256G>C | V86L 2D AIThe SynGAP1 missense variant V86L is reported in ClinVar as “not listed” and is present in the gnomAD database (ID 6‑33425864‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign interpretation, 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. | Likely Benign | 0.685117 | Disordered | 0.552911 | Binding | 0.295 | 0.887 | 0.500 | 6-33425864-G-C | 1 | 6.20e-7 | -3.658 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.081 | Likely Benign | 0.1121 | 0.5386 | -0.84 | Neutral | 0.267 | Benign | 0.097 | Benign | 3.85 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.3913A>C | T1305P 2D AIThe SynGAP1 missense variant T1305P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -1.882 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.204 | Likely Benign | 0.2157 | 0.5386 | -1.41 | Neutral | 0.027 | Benign | 0.114 | Benign | 2.86 | Benign | 0.03 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| c.2062G>C | E688Q 2D AIThe SynGAP1 missense variant E688Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools (premPS and AlphaMissense‑Optimized) give uncertain results and are treated as unavailable. High‑accuracy assessments further show SGM‑Consensus as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as uncertain. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -9.419 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.302 | Likely Benign | 0.1154 | 0.5387 | 0.17 | Likely Benign | 0.9 | 0.15 | Likely Benign | 0.16 | Likely Benign | 0.59 | Ambiguous | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.27 | Benign | 0.15 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| 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 | 0.2383 | 0.5388 | -0.55 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.55 | Benign | 0.16 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.371C>G | A124G 2D AIThe SynGAP1 missense variant A124G 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 the variant being 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.090 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.2433 | 0.5388 | -0.75 | Neutral | 0.934 | Possibly Damaging | 0.447 | Possibly Damaging | 4.06 | Benign | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.847G>C | E283Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The premPS score is uncertain and does not contribute to the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (nine 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 for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -10.650 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.372 | Likely Benign | 0.1432 | 0.5389 | 0.48 | Likely Benign | 0.1 | -0.01 | Likely Benign | 0.24 | Likely Benign | 0.61 | Ambiguous | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1699G>C | E567Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E567Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that agree on a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta’s stability prediction is also uncertain. Overall, more tools (7) predict pathogenicity than benign (5), with three inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -11.302 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.345 | Likely Benign | 0.1029 | 0.5391 | 0.03 | Likely Benign | 0.1 | 1.50 | Ambiguous | 0.77 | Ambiguous | 0.33 | Likely Benign | -2.82 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.47 | Benign | 0.14 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.2524T>A | S842T 2D AIThe SynGAP1 missense variant S842T is not 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy predictors) is Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S842T, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | -13.443 | Likely Pathogenic | 0.725 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | 0.0974 | 0.5391 | -2.23 | Neutral | 0.983 | Probably Damaging | 0.702 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.668C>T | T223I 2D AIThe SynGAP1 T223I variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that clearly indicate benign impact include FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL and PROVEAN. Predictions that are inconclusive (Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of definitive predictions support a benign effect. Thus, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -6.543 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.640 | Likely Pathogenic | 0.0569 | 0.5393 | -0.24 | Likely Benign | 0.8 | -0.99 | Ambiguous | -0.62 | Ambiguous | 0.30 | Likely Benign | -4.09 | Deleterious | 0.010 | Benign | 0.005 | Benign | 5.93 | Benign | 0.07 | Tolerated | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||
| c.704C>T | S235F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors 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 | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -14.456 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.919 | Likely Pathogenic | 0.0617 | 0.5393 | 3.03 | Destabilizing | 1.7 | 0.46 | Likely Benign | 1.75 | Ambiguous | 0.56 | Ambiguous | -5.14 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.552G>C | E184D 2D AIThe SynGAP1 E184D 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 pathogenicity, 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 (six pathogenic vs. three benign predictions) indicates that 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. | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -6.753 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | 0.2249 | 0.5394 | -2.55 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.552G>T | E184D 2D AIThe SynGAP1 E184D 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 pathogenicity, 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 (six pathogenic vs. three benign predictions) indicates that 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. | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -6.753 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | 0.2249 | 0.5394 | -2.55 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.1372A>C | T458P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b, and the SGM‑Consensus) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, 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 | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.547 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.557 | Likely Pathogenic | 0.2098 | 0.5395 | 3.05 | Destabilizing | 0.2 | 5.36 | Destabilizing | 4.21 | Destabilizing | 0.78 | Ambiguous | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.06 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| 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 | 0.1531 | 0.5395 | -2.49 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.899C>A | S300Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300Y has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools (AlphaMissense‑Default and Rosetta) are uncertain and do not influence the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar status (none is available). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -10.464 | Likely Pathogenic | 0.422 | Ambiguous | Likely Benign | 0.116 | Likely Benign | 0.0678 | 0.5395 | -0.08 | Likely Benign | 0.4 | 0.55 | Ambiguous | 0.24 | Likely Benign | 0.28 | Likely Benign | -2.52 | Deleterious | 0.975 | Probably Damaging | 0.686 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.2456C>G | A819G 2D AIThe SynGAP1 missense variant A819G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs three pathogenic) support a benign classification. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.730 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.116 | Likely Benign | 0.2363 | 0.5396 | -2.17 | Neutral | 0.104 | Benign | 0.121 | Benign | 2.29 | Pathogenic | 0.03 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.1014C>A | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.080 | Likely Benign | 0.1584 | 0.5397 | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1014C>G | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.080 | Likely Benign | 0.1584 | 0.5397 | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.2072C>T | T691I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691I is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33441331‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the evidence overwhelmingly indicates that T691I is most likely benign, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | 6-33441331-C-T | 1 | 6.20e-7 | -5.857 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.052 | Likely Benign | 0.0644 | 0.5397 | -1.08 | Ambiguous | 0.1 | -2.12 | Stabilizing | -1.60 | Ambiguous | -0.61 | Ambiguous | -1.19 | Neutral | 0.040 | Benign | 0.003 | Benign | 3.49 | Benign | 0.34 | Tolerated | 3.43 | 14 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||
| c.3929C>T | T1310M 2D  AIThe SynGAP1 missense variant T1310M is listed in ClinVar (ID 2160201.0) as Benign and is present in gnomAD (gnomAD ID 6‑33451803‑C‑T). All evaluated in‑silico predictors report a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | Benign | 1 | 6-33451803-C-T | 17 | 1.05e-5 | -4.822 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 0.1144 | 0.5397 | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||
| c.718G>C | D240H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, 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 Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -14.551 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.865 | Likely Pathogenic | 0.1223 | 0.5398 | 1.14 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.19 | Likely Benign | -6.12 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.2906G>A | G969E 2D  AIThe SynGAP1 missense variant G969E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.721 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.1663 | 0.5399 | -0.10 | Neutral | 0.611 | Possibly Damaging | 0.171 | Benign | 4.28 | Benign | 0.01 | Affected | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||
| c.3301C>T | P1101S 2D AIThe SynGAP1 missense variant P1101S is reported in gnomAD (variant ID 6‑33443853‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | 6-33443853-C-T | 1 | 6.52e-7 | -3.845 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.3265 | 0.5400 | -1.31 | Neutral | 0.626 | Possibly Damaging | 0.255 | Benign | 4.25 | Benign | 0.07 | Tolerated | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.964G>C | A322P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls are made by SGM‑Consensus, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar evidence to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -10.558 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.343 | Likely Benign | 0.2064 | 0.5400 | 1.26 | Ambiguous | 1.3 | 5.43 | Destabilizing | 3.35 | Destabilizing | 0.40 | Likely Benign | -1.72 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.90 | Pathogenic | 0.18 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.2581T>G | S861A 2D AIThe SynGAP1 missense variant S861A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.540903 | Binding | 0.285 | 0.797 | 0.250 | -5.059 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.043 | Likely Benign | 0.4541 | 0.5401 | -1.02 | Neutral | 0.409 | Benign | 0.172 | Benign | 4.08 | Benign | 0.48 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.331C>A | P111T 2D AIThe SynGAP1 missense variant P111T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.800 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.061 | Likely Benign | 0.1650 | 0.5402 | -1.44 | Neutral | 0.421 | Benign | 0.050 | Benign | 4.11 | Benign | 0.02 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| 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 | 0.505 | Likely Pathogenic | 0.1069 | 0.5403 | 2.27 | Destabilizing | 0.3 | 2.33 | Destabilizing | 2.30 | Destabilizing | 0.80 | Ambiguous | -3.95 | Deleterious | 0.994 | Probably Damaging | 0.807 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.2051A>G | D684G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome. Benign predictions come from premPS and FATHMM, whereas the remaining 12 tools—including REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive or missing. 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.238 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.561 | Likely Pathogenic | 0.3686 | 0.5403 | 3.34 | Destabilizing | 1.0 | 4.07 | Destabilizing | 3.71 | Destabilizing | -0.30 | Likely Benign | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.2525C>A | S842Y 2D AIThe SynGAP1 missense variant S842Y is listed in ClinVar as Pathogenic (ClinVar ID 624244.0) and is not reported in gnomAD. Prediction tools that agree on 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. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled 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 indicates that the variant is most likely pathogenic, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | Likely Pathogenic | 1 | -16.124 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | 0.0576 | 0.5403 | -4.28 | Deleterious | 0.944 | Possibly Damaging | 0.676 | Possibly Damaging | 1.97 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||
| c.3280T>G | S1094A 2D AIThe SynGAP1 missense variant S1094A is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -3.595 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.4692 | 0.5403 | -0.78 | Neutral | 0.447 | Benign | 0.252 | Benign | 2.66 | Benign | 1.00 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| 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 | 0.4464 | 0.5405 | -1.03 | Neutral | 0.447 | Benign | 0.139 | Benign | 2.64 | Benign | 0.34 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.605A>G | E202G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic (2 pathogenic, 1 benign, 1 uncertain). Foldetta remains uncertain. Overall, the majority of standard prediction tools suggest a benign effect, and this conclusion does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -8.310 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.259 | Likely Benign | 0.3061 | 0.5405 | 0.37 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.56 | Ambiguous | 0.27 | Likely Benign | -4.70 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||
| c.904T>G | S302A 2D AIThe SynGAP1 missense variant S302A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.583 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.5358 | 0.5407 | Strenghten | 0.21 | Likely Benign | 0.4 | 0.65 | Ambiguous | 0.43 | Likely Benign | 0.02 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.16 | Benign | 0.20 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||
| c.3040G>A | G1014S 2D AIThe SynGAP1 missense variant G1014S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -3.219 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.026 | Likely Benign | 0.2677 | 0.5408 | -0.60 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.95 | Benign | 0.50 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.712G>C | E238Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from SIFT and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. 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 | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -11.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.723 | Likely Pathogenic | 0.1372 | 0.5412 | 0.63 | Ambiguous | 0.5 | 0.59 | Ambiguous | 0.61 | Ambiguous | 0.52 | Ambiguous | -2.72 | Deleterious | 0.996 | Probably Damaging | 0.891 | Possibly Damaging | 5.44 | Benign | 0.06 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.601G>A | D201N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The remaining tools—Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is unavailable because two of the four inputs are uncertain. Foldetta also yields an uncertain result and is unavailable. Overall, the preponderance of evidence points to a benign impact for D201N, 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. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.686 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.160 | Likely Benign | 0.0911 | 0.5413 | 0.31 | Likely Benign | 0.0 | 1.21 | Ambiguous | 0.76 | Ambiguous | -0.10 | Likely Benign | -2.36 | Neutral | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.08 | Benign | 0.13 | Tolerated | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.3527A>G | E1176G 2D AIThe SynGAP1 missense variant E1176G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic 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 show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Overall, the balance of evidence—five benign predictions versus three pathogenic, a consensus leaning benign, and no conflicting ClinVar annotation—suggests that E1176G is most likely benign. 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 | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -4.531 | Likely Benign | 0.838 | Likely Pathogenic | Ambiguous | 0.459 | Likely Benign | 0.2668 | 0.5414 | -2.14 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 5.48 | Benign | 0.08 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.3200C>A | P1067Q 2D AIThe SynGAP1 missense variant P1067Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. 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 points to a benign effect for P1067Q, 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.767 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.136 | Likely Benign | 0.1369 | 0.5415 | -2.39 | Neutral | 0.463 | Possibly Damaging | 0.087 | Benign | 2.84 | Benign | 0.01 | Affected | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.1406C>T | A469V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A469V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and Foldetta; premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts pathogenic. With seven tools supporting pathogenicity versus four supporting benignity, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -8.858 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 0.426 | Likely Benign | 0.0827 | 0.5421 | 2.30 | Destabilizing | 0.4 | 2.66 | Destabilizing | 2.48 | Destabilizing | -0.77 | Ambiguous | 0.26 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.20 | Pathogenic | 0.60 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| c.2051A>C | D684A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only premPS and FATHMM predict a benign outcome. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No evidence 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.547 | Likely Pathogenic | 0.3477 | 0.5423 | 3.34 | Destabilizing | 1.1 | 2.85 | Destabilizing | 3.10 | Destabilizing | 0.28 | Likely Benign | -7.98 | Deleterious | 0.994 | Probably Damaging | 0.758 | Possibly Damaging | 3.42 | Benign | 0.01 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.3589G>A | E1197K 2D AIThe SynGAP1 E1197K missense change is not reported in ClinVar and has no gnomAD entry. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, whereas AlphaMissense‑Optimized predicts it to be Pathogenic; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a benign effect, though the single high‑accuracy pathogenic prediction introduces uncertainty. The variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -5.048 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.364 | Likely Benign | 0.1512 | 0.5424 | -0.27 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.45 | Benign | 0.45 | Tolerated | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.1625A>T | N542I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. Thus, the majority of evidence points to a deleterious effect, with only a minority of tools predicting benign stability. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -14.975 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.829 | Likely Pathogenic | 0.0638 | 0.5427 | 0.14 | Likely Benign | 0.4 | -0.38 | Likely Benign | -0.12 | Likely Benign | 0.42 | Likely Benign | -7.99 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.37 | Pathogenic | 0.02 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.2312C>T | S771F 2D AIThe SynGAP1 missense variant S771F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.988 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.189 | Likely Benign | 0.0624 | 0.5428 | -2.29 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.04 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.0849 | 0.5429 | -3.39 | Deleterious | 0.971 | Probably Damaging | 0.876 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.3037T>C | S1013P 2D AIThe SynGAP1 missense variant S1013P is reported in gnomAD (ID 6‑33443589‑T‑C) 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 classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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 | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | 6-33443589-T-C | 2 | 1.24e-6 | -2.563 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.2338 | 0.5430 | -1.27 | Neutral | 0.453 | Possibly Damaging | 0.150 | Benign | 2.66 | Benign | 0.15 | Tolerated | 3.77 | 5 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.2369C>T | T790I 2D AIThe SynGAP1 missense variant T790I is not 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 predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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, and PROVEAN) is pathogenic. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | -3.556 | Likely Benign | 0.482 | Ambiguous | Likely Benign | 0.190 | Likely Benign | 0.0987 | 0.5431 | -3.08 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.28 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.2995T>G | S999A 2D AIThe SynGAP1 missense variant S999A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -3.719 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.4516 | 0.5434 | -0.83 | Neutral | 0.005 | Benign | 0.016 | Benign | 2.71 | Benign | 0.81 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3122C>A | P1041H 2D AIThe SynGAP1 missense variant P1041H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta’s protein‑folding stability result is unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status because the variant has not been reported there. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -5.312 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.476 | Likely Benign | 0.1883 | 0.5434 | -3.32 | Deleterious | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 5.45 | Benign | 0.03 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.2321C>G | A774G 2D AIThe SynGAP1 missense variant A774G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.129 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.056 | Likely Benign | 0.2392 | 0.5436 | -0.68 | Neutral | 0.135 | Benign | 0.152 | Benign | 4.16 | Benign | 0.22 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3919C>A | P1307T 2D AIThe SynGAP1 missense variant P1307T is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly suggests that P1307T is most likely benign, and this conclusion is consistent with the lack of ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.262 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1732 | 0.5436 | 0.20 | Neutral | 0.386 | Benign | 0.266 | Benign | 3.07 | Benign | 0.60 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2880 | 0.5437 | -1.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.60 | Benign | 0.50 | Tolerated | 3.77 | 5 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.554C>A | S185Y 2D AIThe SynGAP1 missense variant S185Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: 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 majority of computational evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -13.633 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | 0.0736 | 0.5439 | -4.93 | Deleterious | 0.718 | Possibly Damaging | 0.178 | Benign | 3.56 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.1609G>A | A537T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A537T is catalogued in gnomAD (6‑33438852‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote) is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.037313 | Uncertain | 0.928 | 0.362 | 0.000 | 6-33438852-G-A | 2 | 1.24e-6 | -4.704 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.210 | Likely Benign | 0.1520 | 0.5440 | 0.35 | Likely Benign | 0.0 | 0.29 | Likely Benign | 0.32 | Likely Benign | 0.37 | Likely Benign | -1.41 | Neutral | 0.953 | Possibly Damaging | 0.602 | Possibly Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 3.37 | 35 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||
| c.2080G>A | A694T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A694T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the overwhelming majority of evidence indicates a benign effect for A694T, 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 | 0.127496 | Structured | 0.352199 | Uncertain | 0.938 | 0.269 | 0.000 | -3.565 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.1618 | 0.5440 | 0.55 | Ambiguous | 0.1 | 0.11 | Likely Benign | 0.33 | Likely Benign | -0.26 | Likely Benign | -0.71 | Neutral | 0.787 | Possibly Damaging | 0.098 | Benign | 3.46 | Benign | 0.17 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.32G>C | G11A 2D AIThe SynGAP1 missense variant G11A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | -3.611 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.4045 | 0.5440 | -0.28 | Neutral | 0.105 | Benign | 0.007 | Benign | 4.00 | Benign | 0.00 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.1850A>G | E617G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -7.984 | In-Between | 0.777 | Likely Pathogenic | Likely Benign | 0.701 | Likely Pathogenic | 0.2344 | 0.5442 | 0.59 | Ambiguous | 0.2 | 1.60 | Ambiguous | 1.10 | Ambiguous | 0.22 | Likely Benign | -4.99 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.18 | Tolerated | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| 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 | 0.2143 | 0.5442 | -0.05 | Neutral | 0.966 | Probably Damaging | 0.575 | Possibly Damaging | 2.59 | Benign | 0.30 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.2752G>T | A918S 2D AIThe SynGAP1 missense variant A918S is not 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 A918S 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 | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -3.279 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.2824 | 0.5442 | -0.04 | Neutral | 0.910 | Possibly Damaging | 0.554 | Possibly Damaging | 2.66 | Benign | 0.07 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.254C>T | T85I 2D AIThe SynGAP1 missense variant T85I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized also predicts pathogenicity. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that T85I is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.680603 | Disordered | 0.542004 | Binding | 0.288 | 0.888 | 0.500 | -9.310 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.113 | Likely Benign | 0.0634 | 0.5443 | -2.50 | Deleterious | 0.813 | Possibly Damaging | 0.072 | Benign | 3.82 | Benign | 0.00 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.79C>T | P27S 2D AIThe SynGAP1 missense variant P27S is reported in gnomAD (ID 6‑33423488‑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 substitution as benign, and the SGM‑Consensus (derived from the majority of these high‑accuracy predictors) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence indicates that P27S is most likely benign, and this assessment does not contradict any ClinVar classification, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | 6-33423488-C-T | 1 | 6.20e-7 | -2.891 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.3916 | 0.5443 | -2.01 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 4.32 | 1 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.2578G>C | V860L 2D AIThe SynGAP1 missense variant V860L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta 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 | 0.545602 | Disordered | 0.518121 | Binding | 0.269 | 0.803 | 0.250 | -3.053 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.028 | Likely Benign | 0.1052 | 0.5446 | -0.89 | Neutral | 0.124 | Benign | 0.037 | Benign | 4.17 | Benign | 0.00 | Affected | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.2915C>T | P972L 2D AIThe SynGAP1 missense variant P972L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.399 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.020 | Likely Benign | 0.2107 | 0.5447 | -1.73 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.24 | Benign | 0.02 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.3401C>T | T1134I 2D AIThe SynGAP1 missense variant T1134I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -4.072 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.242 | Likely Benign | 0.1071 | 0.5447 | -1.93 | Neutral | 0.453 | Possibly Damaging | 0.162 | Benign | 5.52 | Benign | 0.44 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.3734A>G | E1245G 2D AIThe SynGAP1 missense variant E1245G is 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 assessment shows AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (derived from the 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 points to a pathogenic effect; 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 | 0.712013 | Disordered | 0.387847 | Uncertain | 0.869 | 0.554 | 0.625 | -12.113 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.299 | Likely Benign | 0.2145 | 0.5447 | -5.65 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.4000A>T | N1334Y 2D AIThe SynGAP1 missense variant N1334Y is not 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, whereas pathogenic predictions are made by 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—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive; Foldetta results are unavailable. Overall, the majority of conventional tools predict a pathogenic impact, but the single high‑accuracy benign prediction and the inconclusive consensus suggest uncertainty. Consequently, the variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict any ClinVar annotation because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -5.916 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | 0.0716 | 0.5447 | -4.62 | Deleterious | 0.985 | Probably Damaging | 0.852 | Possibly Damaging | 3.49 | Benign | 0.00 | Affected | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||
| c.56C>G | A19G 2D AIThe SynGAP1 missense variant A19G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | -3.525 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.2324 | 0.5447 | -0.45 | Neutral | 0.371 | Benign | 0.036 | Benign | 4.10 | Benign | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3413C>A | S1138Y 2D AIThe SynGAP1 missense variant S1138Y is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (ID 6‑33444448‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM Consensus both indicate a benign outcome, while Foldetta data are missing. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This benign prediction does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | Uncertain | 1 | 6-33444448-C-A | 3 | 1.86e-6 | -6.610 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.391 | Likely Benign | 0.1034 | 0.5449 | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.41 | Benign | 0.05 | Affected | 4.32 | 4 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2488C>T | P830S 2D AIThe SynGAP1 missense variant P830S is not 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, 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 there is no ClinVar classification to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.618152 | Binding | 0.333 | 0.874 | 0.500 | -4.629 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.219 | Likely Benign | 0.3496 | 0.5450 | -3.23 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.28 | Tolerated | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3101C>A | P1034H 2D AIThe SynGAP1 missense variant P1034H is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.634 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.083 | Likely Benign | 0.1776 | 0.5451 | -3.17 | Deleterious | 0.938 | Possibly Damaging | 0.750 | Possibly Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3211G>A | G1071S 2D AIThe SynGAP1 missense variant G1071S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1071S, 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 | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -1.139 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.093 | Likely Benign | 0.2468 | 0.5451 | -1.06 | Neutral | 0.692 | Possibly Damaging | 0.222 | Benign | 4.10 | Benign | 0.28 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.344A>T | Q115L 2D AIThe SynGAP1 missense variant Q115L 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 not available. Overall, the majority of evidence points to a benign effect for Q115L, 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.281 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.123 | Likely Benign | 0.0710 | 0.5452 | -1.25 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.10 | Benign | 0.10 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3809A>G | E1270G 2D AIThe SynGAP1 missense variant E1270G is listed in gnomAD (ID 6‑33447857‑A‑G) and 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, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic, while Foldetta’s protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the absence of a benign consensus, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | 6-33447857-A-G | -12.022 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.385 | Likely Benign | 0.2415 | 0.5452 | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||
| c.1562A>G | E521G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E521G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split and is treated as unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign 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. | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -6.636 | Likely Benign | 0.767 | Likely Pathogenic | Likely Benign | 0.289 | Likely Benign | 0.2932 | 0.5455 | 0.18 | Likely Benign | 0.1 | 0.58 | Ambiguous | 0.38 | Likely Benign | 0.14 | Likely Benign | -3.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||
| c.2453C>A | P818Q 2D AIThe SynGAP1 missense variant P818Q is not listed in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that P818Q 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 | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -6.855 | Likely Benign | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.303 | Likely Benign | 0.1569 | 0.5456 | -4.07 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 1.97 | Pathogenic | 0.27 | Tolerated | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.1265A>T | E422V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E422V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. FoldX remains uncertain. Overall, the majority of high‑confidence tools lean toward pathogenicity, 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 | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -12.371 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.489 | Likely Benign | 0.0609 | 0.5457 | 0.90 | Ambiguous | 0.1 | -0.02 | Likely Benign | 0.44 | Likely Benign | 0.24 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1484A>T | E495V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence (10 pathogenic‑predicted tools versus 4 benign) indicates that E495V is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -12.031 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.887 | Likely Pathogenic | 0.0646 | 0.5457 | 0.43 | Likely Benign | 0.2 | -0.32 | Likely Benign | 0.06 | Likely Benign | 0.47 | Likely Benign | -6.83 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.16G>T | A6S 2D AIThe SynGAP1 missense variant A6S is reported in gnomAD (variant ID 6-33420280‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.566480 | Disordered | 0.549054 | Binding | 0.377 | 0.920 | 0.875 | 6-33420280-G-T | -2.485 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.2720 | 0.5457 | 0.06 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||
| c.2788C>T | P930S 2D AIThe SynGAP1 missense variant P930S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to 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 AlphaMissense‑Optimized all 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 is pathogenic, and the SGM‑Consensus is Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that P930S 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 | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -8.439 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.379 | Likely Benign | 0.3301 | 0.5457 | -5.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.1757A>T | D586V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D586V 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 FoldX, Rosetta, Foldetta, premPS, and SIFT. Tools that predict pathogenicity include SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (nine pathogenic vs. five benign) indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -12.409 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.801 | Likely Pathogenic | 0.0826 | 0.5458 | 0.40 | Likely Benign | 0.2 | 0.03 | Likely Benign | 0.22 | Likely Benign | 0.18 | Likely Benign | -5.58 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | -1.23 | Pathogenic | 0.24 | Tolerated | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.3959C>A | P1320H 2D AIThe SynGAP1 missense variant P1320H is listed in gnomAD (ID 6‑33451833‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. 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 | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451833-C-A | 2 | 1.29e-6 | -6.296 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.114 | Likely Benign | 0.1955 | 0.5461 | -1.05 | Neutral | 0.998 | Probably Damaging | 0.990 | Probably Damaging | 4.17 | Benign | 0.00 | Affected | 3.77 | 5 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||
| c.196C>T | P66S 2D AIThe SynGAP1 missense variant P66S is listed in ClinVar (ID 1915017.0) as benign and is present in gnomAD (variant ID 6‑33425804‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, which is consistent with the ClinVar designation and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | Benign | 1 | 6-33425804-C-T | 2 | 1.24e-6 | -2.760 | Likely Benign | 0.929 | Likely Pathogenic | Ambiguous | 0.081 | Likely Benign | 0.3417 | 0.5463 | -1.69 | Neutral | 0.909 | Possibly Damaging | 0.641 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||
| 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 | 0.1136 | 0.5464 | -2.22 | Neutral | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.60 | Benign | 0.05 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2977C>T | P993S 2D AIThe SynGAP1 missense variant P993S is reported in gnomAD (ID 6‑33443529‑C‑T) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenicity, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | 6-33443529-C-T | 3 | 1.86e-6 | -3.665 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.3421 | 0.5465 | -0.13 | Neutral | 0.011 | Benign | 0.023 | Benign | 4.26 | Benign | 0.59 | Tolerated | 4.32 | 2 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3511G>A | A1171T 2D AIThe SynGAP1 missense variant A1171T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | Uncertain | 1 | -3.658 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.201 | Likely Benign | 0.1421 | 0.5465 | -0.48 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.45 | Benign | 0.07 | Tolerated | 4.32 | 4 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.781G>C | D261H 2D AIThe SynGAP1 missense variant D261H 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 premPS and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic 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 Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -13.688 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.780 | Likely Pathogenic | 0.0937 | 0.5465 | 4.33 | Destabilizing | 3.2 | 0.93 | Ambiguous | 2.63 | Destabilizing | 0.33 | Likely Benign | -3.67 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 6.04 | Benign | 0.01 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.2803G>C | A935P 2D AIThe SynGAP1 missense variant A935P is not 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, polyPhen‑2 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. | 0.736850 | Disordered | 0.980490 | Binding | 0.286 | 0.865 | 0.625 | -3.239 | Likely Benign | 0.371 | Ambiguous | Likely Benign | 0.269 | Likely Benign | 0.2062 | 0.5466 | -2.08 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||
| c.1018G>C | A340P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A340P 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, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy predictors—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—each report a benign outcome. No prediction or folding‑stability result is missing or inconclusive; all available evidence points to a benign impact. Consequently, the variant is most likely benign based on the aggregate 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 Benign | C2 | 0.390993 | Structured | 0.410781 | Uncertain | 0.558 | 0.485 | 0.250 | -4.983 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.279 | Likely Benign | 0.2178 | 0.5468 | 0.32 | Likely Benign | 0.5 | -0.58 | Ambiguous | -0.13 | Likely Benign | 0.46 | Likely Benign | -1.48 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 1.91 | Pathogenic | 0.25 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| 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 | 0.0834 | 0.5468 | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.923 | Probably Damaging | 2.50 | Benign | 0.04 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.2586C>A | N862K 2D AIThe SynGAP1 missense variant N862K 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 from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -7.000 | In-Between | 0.766 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | 0.2313 | 0.5469 | -1.87 | Neutral | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 4.10 | Benign | 0.20 | Tolerated | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||
| c.2586C>G | N862K 2D AIThe SynGAP1 missense variant N862K 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 from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -7.000 | In-Between | 0.766 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | 0.2313 | 0.5469 | -1.87 | Neutral | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 4.10 | Benign | 0.20 | Tolerated | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||
| c.581A>T | E194V 2D AIThe SynGAP1 missense variant E194V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of computational 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -10.261 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.284 | Likely Benign | 0.0623 | 0.5469 | -4.67 | Deleterious | 0.580 | Possibly Damaging | 0.254 | Benign | 3.94 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.2864C>G | S955C 2D AIThe SynGAP1 missense variant S955C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (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 available predictions (5 pathogenic vs. 4 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -8.675 | Likely Pathogenic | 0.117 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.1741 | 0.5470 | -1.48 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.2867C>G | S956C 2D AIThe SynGAP1 missense variant S956C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -9.292 | Likely Pathogenic | 0.108 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.1833 | 0.5470 | -0.34 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.2941G>A | G981S 2D AIThe SynGAP1 missense variant G981S is not reported in ClinVar and is absent from 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) 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—including the consensus and high‑accuracy tools—points to a benign effect. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.970320 | Binding | 0.275 | 0.897 | 0.625 | -2.749 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.130 | Likely Benign | 0.2566 | 0.5470 | -0.57 | Neutral | 0.979 | Probably Damaging | 0.907 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3811G>C | E1271Q 2D AIThe SynGAP1 missense variant E1271Q is 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. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.085 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.175 | Likely Benign | 0.0955 | 0.5470 | -2.40 | Neutral | 0.951 | Possibly Damaging | 0.617 | Possibly Damaging | 2.06 | Pathogenic | 0.00 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.1229G>A | S410N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410N is predicted to be benign by all evaluated in‑silico tools. Consensus predictors (REVEL, SIFT, polyPhen‑2 HumDiv/HumVar, PROVEAN, premPS, FoldX, Rosetta, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly report a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies it as “Likely Benign.” High‑accuracy assessments likewise support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a benign effect. ClinVar contains no entry for this variant, and it is not present in gnomAD. Based on the collective predictions, 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 | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -2.901 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.1310 | 0.5471 | -0.16 | Likely Benign | 0.1 | -0.16 | Likely Benign | -0.16 | Likely Benign | 0.38 | Likely Benign | -0.91 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.18 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||
| c.2657C>T | A886V 2D AIThe SynGAP1 missense variant A886V is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443209‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.619166 | Binding | 0.359 | 0.922 | 0.500 | Uncertain | 1 | 6-33443209-C-T | 18 | 1.12e-5 | -4.478 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.061 | Likely Benign | 0.1131 | 0.5471 | -0.20 | Neutral | 0.888 | Possibly Damaging | 0.314 | Benign | 2.17 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||
| c.386C>G | S129W 2D AIThe SynGAP1 missense variant S129W is not 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, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is 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. 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 | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -5.008 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | 0.0523 | 0.5471 | -1.49 | Neutral | 0.888 | Possibly Damaging | 0.367 | Benign | 4.06 | Benign | 0.01 | Affected | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.1051G>C | A351P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are Foldetta, PROVEAN, SIFT, FATHMM, and Rosetta. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar reporting; thus the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.559 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.1862 | 0.5472 | -0.89 | Ambiguous | 0.2 | 6.19 | Destabilizing | 2.65 | Destabilizing | 0.62 | Ambiguous | -3.08 | Deleterious | 0.016 | Benign | 0.007 | Benign | 1.67 | Pathogenic | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| c.1195G>C | A399P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A399P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic effect. Overall, the majority of evidence points toward a deleterious impact. The variant is most likely pathogenic based on the available 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. | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -8.809 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 0.498 | Likely Benign | 0.1847 | 0.5472 | 2.29 | Destabilizing | 0.1 | 4.00 | Destabilizing | 3.15 | Destabilizing | 0.74 | Ambiguous | -1.82 | Neutral | 0.596 | Possibly Damaging | 0.188 | Benign | 5.56 | Benign | 0.10 | Tolerated | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| 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 | 0.1167 | 0.5472 | -2.75 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.59 | Benign | 0.06 | Tolerated | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.2905G>A | G969R 2D AIThe SynGAP1 missense variant G969R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | 0.1039 | 0.5473 | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2905G>C | G969R 2D AIThe SynGAP1 missense variant G969R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | 0.1039 | 0.5473 | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3601G>C | E1201Q 2D AIThe SynGAP1 E1201Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -4.415 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | 0.0769 | 0.5473 | -2.44 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.62 | Pathogenic | 0.03 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3134C>T | A1045V 2D AIThe SynGAP1 missense variant A1045V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -4.229 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.035 | Likely Benign | 0.1487 | 0.5474 | -0.35 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.06 | Benign | 1.00 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.781G>T | D261Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D261Y 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 premPS and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No prediction or folding stability result is missing or inconclusive beyond the stated uncertainties. Overall, the preponderance of evidence points to a pathogenic effect for D261Y, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -14.961 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.886 | Likely Pathogenic | 0.0474 | 0.5476 | 2.93 | Destabilizing | 2.1 | 0.81 | Ambiguous | 1.87 | Ambiguous | -0.12 | Likely Benign | -5.50 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.73 | Benign | 0.01 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.864C>A | D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -6.685 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.203 | Likely Benign | 0.1559 | 0.5476 | 0.10 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.42 | Likely Benign | -0.10 | Likely Benign | -2.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.13 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.864C>G | D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -6.685 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.203 | Likely Benign | 0.1559 | 0.5476 | 0.10 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.42 | Likely Benign | -0.10 | Likely Benign | -2.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.13 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.2429G>C | R810P 2D AIThe SynGAP1 missense variant R810P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant 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 points to a pathogenic impact for R810P. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -4.120 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.316 | Likely Benign | 0.2307 | 0.5478 | -4.08 | Deleterious | 1.000 | Probably Damaging | 0.977 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.3194C>A | P1065Q 2D AIThe SynGAP1 missense variant P1065Q 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. 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 | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -3.928 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.026 | Likely Benign | 0.1487 | 0.5478 | -2.44 | Neutral | 0.102 | Benign | 0.057 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
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